Experimental Hematology
Volume 36, Issue 11 , Pages 1403-1416, November 2008

Final checkup of neoplastic DNA replication: Evidence for failure in decision-making at the mitotic cell cycle checkpoint G1/S

  • Gregor Prindull

      Affiliations

    • Corresponding Author InformationOffprint requests to: Gregor Prindull, M.D., University of Göttingen, Department of Pediatrics, Robert-Koch-Strasse 4, Göttingen, 37075, Germany

Department of Pediatrics, University of Göttingen, Göttingen, Germany

Received 18 June 2008; received in revised form 29 July 2008; accepted 29 July 2008.

Article Outline

Objectives

Processing of epigenomic transcriptional information by cell cycle phase G1 and decision-making at checkpoint G1/S are the final organizational steps preceding gene replication in transcriptional reorientation programs (i.e., switches from proliferation to cycle arrest and neoplastic transformation). Further analyses of cycle progression will open up new approaches in antineoplastic therapy.

Materials and Methods

The following bibliographic databases were consulted: Central Medical Library Cologne, PubMed (English), the last search was done on April 23,2008 and key words searched were: cell cycle, cell memory, DNA methylation, embryonal/neoplastic stem cells, enzyme-modulated chromatin, G1-G1/S checkpoint, genomic/epigenomics, genomic viral DNA, histones, telomere/telomerases, transcription factors, neoplastic transformation, senescence.

Results

Gene transcription and epigenomic surveillance form a functional entity. In proliferation programs, transcriptional information is mediated by chromatin and DNA methylation, analyzed and processed in G1 phase, and converged on the parental checkpoint G1/S for final decision-making on DNA replication. Genomic reorientation appears to be associated with transcriptional instability, which normally is corrected, possibly during the G2/M phase, to new levels of epigenomic equilibria. We speculate that daughter stem cells inherit persistent neoplasm-specific transcriptional instabilities through failure of the parental G1/S checkpoint. Foreign, silenced, potentially oncogenic DNA sequences, i.e. regular components of the human genome such as endogenous retroviruses, could conceivably be activated for expression in neoplastic transformation by epigenomic histone deacetylase/acetyl transferase/histone methyltransferase-mixed lineage leukemia deregulations.

Conclusions

Failure of cell cycle G1/S decision-making for DNA replication is the final and possibly a major cause in neoplastic transformation. Therefore, further analysis of the dynamics of G1-G1/Sphases could provide new opportunities for therapeutic strategies.

 

Transcriptional stability is a basic requirement for maintenance of eukaryotic cell life. It has two components—genomic and epigenomic—which, together, form a functional entity. Epigenomic mechanisms secure stability of gene transcription by close guidance of the access of transcription factors to proliferation- and differentiation-bound genes employing fine-tuned adjustments in chromatin arrangements and DNA methylation 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. The preeminent role of epigenomic control in transcriptional stability has been well documented in nuclear transfer experiments 14, 15, 16, 17 where deregulated coordination between oocytic cytoplasmic factors and highly differentiated somatic cell nuclei frequently interfere with regular cell cycle progression. This results in failure to establish stabile transcriptional programs in attempts to generate pluripotent stem cell populations and may lead to cell death or neoplastic transformation 18, 19. Interestingly, in neoplasms, transcriptional deregulation does not affect single genes accidentally but rather involves entire sets of tumor-associated genes in a nonrandom manner 10, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. This emphasizes the role of the cell cycle in genomic reorientation of both regular and neoplastic transcription programs. We decided to look at the dynamics of cell cycle phases G1-G1/S, which are the regular epigenomic control points that secure faithful DNA replication in S-phase 29, 30, 31, 32, 33, 34, 35, 36. We speculate that checkpoint G1/S and the preceding G1 phase are strategic steps in transcriptional decision-making, which might also be of major pathogenetic importance in neoplastic transcriptional gene reorientation 12, 13, perhaps as targets for therapeutic strategies.

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Clinical examples of epigenomic transcriptional instability 

Epigenomics are involved in the pathogenesis of a variety of human diseases 37, 38, 39, which are frequently associated with increased risks of tumorigenesis. Examples include functional restrictions of aging stem cells and diseases of accelerated aging 28, 40, 41; abnormal gestational environments of premature/small-for-date infants and in artificial fertilization both associated in later childhood with reduced life expectancies and increased morbidity rates, including neoplasms 39, 42, 43, 44, 45; embryos cloned by nuclear transfer causing severe pre- and postnatal morbidity/mortality 14, 15, 16, 17, 46, 47; discordant DNA transcription patterns between identical twins after prolonged separation in different environments 48, 49, 50; checkpoint adaptation of cells under DNA repair escaping epigenomic p53/Rb-mediated control 51, 52, 53 by resuming proliferation in spite of persisting DNA damage 35, 54; and classification of neoplasms as epigenomic diseases 21, 25, 55, 56, 57. In the latter, three steps have been suggested to set the molecular stage for neoplastic transformation in progenitor cells [58]: epigenomic control, gene mutations, and instabilities of “epigenomic gatekeepers” fostering tumor progression 25, 57. Because each type of neoplasm has its own stem cell signature [59], future therapeutic protocols will have to be adjusted for these specificities in every new cancer patient at diagnosis and, importantly, during disease progression.

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Transcriptional instabilities in embryonal stem cells 

Epigenomic transcriptional instability with innate potentialities for neoplastic transformation is particularly high in early embryonal developmental programs [15]. The majority of embryonal stem (ES) cells rapidly proceed to transcriptional gene reorientation and undergo polycomb-induced differentiation through mitotic divisions. Only a minority subpopulation of ES cells is maintained in a state of pluripotency 60, 61, 62. Transcriptional instabilities contributing to accelerated progression of ES cell cycles are promoted by shortened or absent cell cycle G1 phases, reduction of S phase to 2 hours’ duration, low levels of activated Rb and delayed cycle arrest in response to overexpression of p16INK4A 63, 64. Instabilities produce two waves of apoptotic scrutiny, both reflecting transcriptional reorientation: The first is seen in 4/8 cell human embryos that start transcribing their own genes after cessation of maternal mRNA functions 60, 61, 62, 65, 66, 67. A second apoptotic wave follows at gastrulation (around <10 weeks of gestation) when organ-specific gene transcription programs are introduced by DNA methyltransferase (DNMT)–mediated de novo DNA methylation 40, 68, 69. Additional transcriptional genomic/epigenomic instabilities occur in ES cells at checkpoint G2/M by uncoupling of apoptosis from anaphase 15, 27, 67, 70, 71 and may be associated with transitory instabilities in transcriptional reorientation programs, as discussed below. This corresponds to apoptotic uncoupling in neoplastic transformation of embryonal and postnatal stem cells 27, 72, 73, 74, 75, 76 and results in unequal distribution of genetic materials to daughter cells 26, 55, 70, 72, 74, 77.

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Epigenomics and cell memory 

Cell memory is a basic requirement for epigenomic stability. Memory mechanisms preserve parental developmental decisions over multiple cell generations as silenced, gene-specific transcriptional profiles stored in cyclin-dependent heterochromatin-engraved complexes which they communicate through mitotic cell cycles to daughter cells for later retrieval (Fig. 1) 25, 78, 79, 80, 81, 82. Before reaching the cell cycle at G1, transcriptional information is preprocessed by histone code-modified chromatin arrangements and by DNA methylation 78, 83, 84, 85. Key epigenomic chromatin modifiers are polycomb/trithorax (PcG/TrxG) proteins 86, 87, 88, 89, 90, transcription factors E2F 91, 92, and RNA interference 93, 94, 95. PcG/TRxG are evolutionary conserved methyltransferases containing a HMTs-SET domain with a CpG-binding CXXC finger protein. The core function of SET domains probably is associated with histone tail-binding and requires additional specializations for methyltransferase activity [87]. Two groups of PcG/TrxG, proto-oncogenes Ezh2 and bmi1, introduce long-term developmental decision-making for epigenomic memory inheritance 60, 62: Methyltransferase Ezh2 is involved in tumor-suppressive INK4A gene-silencing programs 96, 97 and connects specific chromatin-modified information to transcription-regulating complexes of de-novo methylated CpG sites 89, 98, 99, 100. bmi1s are zinc finger, E2F-dependent transcriptional repressor proteins that mediate deposition of information as heterodimers onto replicated DNA strands and mark INK4A/ARF and HOX genes for repressive signals of heritable transmission 87, 89, 101, 102. (For details on chromatin modifiers: see below, section: chromatin structuration).

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  • Figure 1 

    Transcriptional inheritance of cell memory (oversimplified). Parental cell: Transcriptional information on an earlier developmental decision is epigenomically preprocessed and inactivated. Mitosis: The inactivated information is stored in condensed heterochromatin. The parental cell divides into daughter cells both receiving a complete set of stored transcriptional information. Daughter cells: Stored information is either transcriptionally reactivated in decondensed chromatin by epigenomic factors and is ready to participate in the next cell cycle as transcribable signals (left branch). Alternatively, transcriptional signals remain postmitotically inactivated, stored in heterochromatin and will be presented as such to the next mitotic cell division (right branch).

G1 phase and the G1/S checkpoint are the final steps for the detection and elimination of transcriptional abnormalities before DNA replication is initiated. In regular cell cycles, premitotic scrutiny during G1 depends, for example, on epigenomic differentiation-associated tumor suppressors, e.g. PcG/TRxG proteins 60, 62, 103 from non-/antineoplastic memory information, which eliminate transcription-deregulating factors, such as ectopic leukemic cell fusion products 22, 59, 104. However, in the pathogenesis of certain tumors, pretranscriptional failure at G1-G1/S will allow nonneoplastic daughter stem cells and stromal cells [104] to inherit neoplastic potentialities by mitotic acquisition: In contrast to regular cell cycles, these cells appear to activate parental neoplastic memory information in successive steps during repeated cycle passages 21, 24, 25, 36, 55, 56, 57 that will eventually lead to replication of neoplasia-associated genes during S phase 1, 20, 59, 105, 106. Alternatively, certain pediatric leukemias appear to undergo neoplastic transformation as a primary event in early ES cells 75, 76.

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Effects of telomeres/telomerases on G1-G1/S phases of the cell cycle 

Telomeres/telomerases play important roles in the control of cell proliferation, not only in senescence but also in neoplastic growth [107]. Telomeres shortened down to a critical length of 4 to 7kb (from a normal of 15–20 kb in humans) profoundly affect the processing of transcriptional information by cycle G1 and G1/S 108, 109, 110, 111, 112. Shortening is involved in genomic instability of senescence, impaired cell viability 113, 114, age-accelerating diseases [115] and neoplastic transformation [109]. Short telomeres induce irreversible cycle arrest and apoptosis by DNA-CpG methylation, activation of p53/pRb, and CDKIs p21, p16, p14, p15. They inhibit G1 progression [116] and modulate chromatin histone codes (e.g., at H3Lys4,9 and H4Lys20) [108]. Disruption of gene-specific, histone deacetylase (HDAC)–mediated chromatin deacetylation inhibits binding of mixed lineage leukemia (MLL) (a histone H3Lys4 methyltransferase) to telomeric complexes. This denies access of transcription factors to telomerase genes 117, 118, 119, 120 and results in net losses of telomere repeats 121, 122, 123, abrogation of cycle-dependent telomerase-catalyzed resynthesis of telomere nucleotides in senescence programs 124, 125, and of tumor suppressor functions 117, 126. On the other hand, high telomerase activity in conjunction with genomic instability promotes neoplastic transformation 109, 127, 128, 129, 130. Synthetic telomerase-inhibitors, such as azidothymidine block elongation of telomeres by phosphorylating DNA sequences and accelerate losses of telomere repeats in pre-/neoplastic stem cells 131, 132, 133, 134.

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Signals for G1/S decision-making 

Accessibility of transcription factors to the cell cycle is determined by preprocessing of transcriptional information in G0 through DNA methylation and chromatin stucturation 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145. During passage through G1 phase, which may vary considerably in duration, a wealth of transcription-relevant information is scrutinized, condensed, and presented to checkpoint G1/S for signal identification and final decision-making on whether or not the cell is to be admitted to S-phase for DNA replication (Fig. 2). For example, signals from neoplasm-associated genes activate during G1 the ATM/ATR (ataxia telangiectasia mutated/ataxia telangiectasia related proteins, i.e. DNA damage response PIKK protein kinases)-regulated G1/S checkpoint as an antineoplastic barrier in attempts to safeguard genomic integrity 36, 80, 146, 147. Cell cycle dynamics are regulated by bidirectional equilibria of cyclins, their cyclin-dependent kinases (CDKs), and their inhibitors (CDKI), the levels of which undulate during cycle progression as a result of degradation by the ubiquitin-proteasome system [139]. Cyclins D-CDK4/6 and E-CDK2 drive G1 and G1/S transitions. Cyclin levels are low in early G1, and rise to full activity in late G1 and G1/S [148]. Preparatory steps for passage of the G1/S checkpoint include disruption of nucleosome structures through SWI/SNF (an adenosine triphosphate–dependent chromatin-remodeling complex) complexes 149, 150, and the assembly of transcriptional polypeptides by RNA polymerase II (RNA-Poly II) at every promotor gene 151, 152. Activation of RNA-Poly II is, indeed, of particular functional significance since gene regulation is executed predominantly at the level of DNA templates and RNA-Poly II is responsible for all mRNA synthesis [153]. When CDKI p16 and p27 are downregulated and MLL methyltransferases are degraded (together with inactivation of pRb) cyclin E/CDK2 levels increase again and marshal cell transit through G1/S to enter S-phase 154, 155.

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  • Figure 2 

    Signal presentation to G1/S transition of the cell cycle: Hypothesis. G0 phase: Generation of transcriptional signals—Epigenomic processing of transcriptional information through chromatin modifiers, DNA methylation status, etc. G0/G1 transition: Entry of the cell cycle by transcriptional signals. G1 phase: Signals are identified, filtered, and condensed to a single command (or to a limited number of commands) for presentation to G1/S transition. G1/S transition: Final decision-making whether the cell should be allowed to enter S-phase for DNA replication or, alternatively, be rejected for cycle arrest, senescence, or neoplastic transformation.

Inhibition and arrest of G1 progression are important in transcriptional safety. They are induced by CDKI proteins p16INK4A, p14/p19ARF, p15INK4B, and p21Sdi1,Cip1,Waf1, p27Kip1, respectively, of suppressor genes INK4A/ARF and Cip/Kip 148, 156, 157, 158, 159. p16/p19 form complexes with transcription repressors E2F4,5, establish links to gene-specific tumor suppressor pathways pRb and p53, induce cell cycle arrest, and are also involved in overlapping pathways in cell immortalization 159, 160, 161, 162, 163. Loss of p16 induces transcriptional instabilities and proliferation of pre-/neoplastic cells 97, 164, 165 identifying p16 is a major tumor suppressor protein. p15 links cyclin D-CDK4/6 inhibition to telomere functions [166]. Because abnormalities of gene transcription are of major pathogenetic importance in numerous human diseases, including genetic instabilities of neoplasms 26, 138, 167, 168, 169, 170, arrest of the cell cycle should occur prior to DNA replication, i.e., at G1-G1/S, to be effective as a protective measure against faulty gene expression. Arrest may be irreversible in response to major DNA abnormalities, or temporary to allow sufficient time for the completion of reparative steps of damaged DNA. Inadequate repair, e.g. in checkpoint adaptation, can result in premature release from cycle arrest and, through overexpression of cyclin E-CDK2, in transcriptional deregulation and neoplastic DNA replication 35, 54. Synthetic anticancer CDKI-drugs block abnormal cell cycle progression 171, 172, 173 or reactivate p53-dependent senescence by inhibition of telomeres/telomerase activity, and increase expression of CDKI proteins 131, 132, 133, 134.

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Transcription repressors/tumor suppressors 

Major tumor suppressors are pRb, p53, E2F, and TIS21/BTG2/PC3 that operate in synergy with CDKI. They are integral components of an elaborate network for transcriptional decision-making at G1-G1/S checkpoint 174, 175, 176, 177. Expression of pRb is initiated early in G1 (by hypophosphorylation at position Ser 780) [169]. It directly activates suppressor genes INK4A/ARF 151, 152 and E2F4,5-repressive promotors [137]; inactivates catalytic activities of cyclins E-CDK2 and D1-CDK4/6, and temporarily blocks G1 progression 175, 176, 177, 178, 179. pRb also regulates polycomb-mediated DNA hypermethylation and suppresses proliferation-promoting E2F1-3-responsive genes 180, 181. Arrest of cycle progression is relinquished by inactivation of pRb late in G1, so that repression of E2F1-3 complexes is alleviated and cycles progress to S-phase [137]. Importantly, pRb also affects cell cycles of auxiliary genes.

p53 pathways are multifunctional in maintaining transcriptional genomic/epigenomic stability and likewise control auxiliary genes: They target cycle phase-controlling genes, in functional balances with their inhibitor MDM2, and reduce cyclin/CDKs levels 98, 182, 183, 184, 185, 186. With its downstream effector p21, p53 initiates cell cycle arrest at G1, even prior to expression of the key regulator of cell cycle arrest, p16 63, 152, 182. Together with p15, p53 prolongs G1 phase, represses DNA methylation by DNMT1 through specific DNA binding 187, 188, reacts to telomere attrition by promoting telomere-associated replicative stem cell senescence, and contributes to DNA damage repair 34, 121, 147, 168, 187. Furthermore, p53 mediates transforming growth factor–β1-induced apoptotic growth arrest downstream of the pRb/E2F pathway [183] and regulates epigenomic chromatin surveillance through suppression of histone methyltransferase polycomb Ezh2 [98]. (For additional information on chromatin arrangements and DNA methylation in early stages of the cell cycle, see below, section: chromatin structuration).

Members of the E2F family are transcription regulators that affect the cell cycle in opposing manners. They have coordinating functions on G1-G1/S cycle progression, integrate DNA replication and repair 91, 92, 189, connect chromatin-modifying histone enzymes to cycle progression, and regulate access of transcription factors to DNA replication 92, 190, 191. E2F1-3 are constitutive transcription activators of proliferation-bound genes. They trigger promotor genes for cell entry into G1 and transition of checkpoint G1/S 91, 92, 181. When unbalanced by pRb, overexpressed E2F1 synergizes with oncogenes, triggers quiescent cells to enter proliferative cycles and to participate in neoplastic invasion, metastasis, and angiogenesis 181, 191. On the other hand, E2F4,5 are transcription repressors 137, 189. E2F4,5 silence E2F1-3 targeted genes 152, 180, 181, form complexes with p53/pRb and p16/p19 to prevent cell entry into S-phase 162, 192, 193, 194, induce cell differentiation at G1/S 91, 92, 149, 189, 190, and inhibit uncoupling of proliferative from tumor-suppressive pathways 162, 163, 189, 195 in senescent pre-neoplastic cells 33, 34.

Among other transcription regulating factors, TPA-inducible early growth response gene TIS21/BTG2/PC3 is noteworthy as a pan-cell cycle tumor suppressor and endogenous cell death molecule that acts at both G1/S and G2/M checkpoints. It represses cyclin D1, regulates proliferation-suppressive pRb/p16 pathways, and inhibits early phase neoplastic transformation at G1/S. Even in tumor cells in which pRb/p53 is inactivated, TIS21 still inhibits degradation of cyclins A/B1, binds directly to CDK2 and induces tumor cell senescence/apoptosis [177]. Thus, therapeutically induced overexpression of TIS21 might shift neoplastic transformation processes towards innate cell senescence.

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Chromatin structuration through modifications by histone enzymes—Preprogramming of transcriptional information 

Incoming transcriptional signals at G1 originate from chromatin arrangements 141, 142, 144, 145 and from DNA methylation 135, 136, 143. (For the latter, see section: DNA CpG and non-CpG methylation). Chromatin signals control access of transcription factors to gene promotors 28, 140, 141, 142, 143, 144, 145, 196, 197, and are further processed during G1 cell passage. Indeed, a multitude of chromatin signals reach G1 where, most likely, they are processed, identified, selected, filtered, condensed, and converged on to the G1/S checkpoint (Fig. 2). Based on this information, the checkpoint then makes the decision whether the cell should be allowed to proceed in cycle to S phase for regular DNA replication, or to undergo differentiation, cycle arrest, senescence, or, possibly, suffer neoplastic transformation (Fig. 3). Thus, G1-G1/S collaborate in key positions in regular and neoplastic cell fate. The other major control mechanisms against neoplastic transformation, namely G2 phase and G2/M checkpoint of the cell cycle, are not considered here.

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  • Figure 3 

    Transcriptional instability: transitory in cell senescence/cycle arrest vs permanent in neoplastic transformation. Incoming epigenomic signals from histone-mediated chromatin arrangements and DNA methylation are processed during G1 passage and presented as transcriptional information to parental checkpoint G1/S for decision-making on DNA replication, see Figure 2. Messages to regular transcriptional reorientation programs (differentiation, cycle arrest, senescence) to nonneoplastic daughter cells seem to be associated with transient transcriptional instabilities (symbolized by the red crescent in the left daughter cell); new levels of transcriptional stability are rapidly established, possibly during G2/M phase. In a few stem cells, however, failure or abnormal G1/S decision-making leads to persistence of epigenomic/genomic transcriptional instabilities/deregulations involving entire sets of pathogenetic neoplasm-associated genes (right daughter cell) and may initiate the expression of neoplastic transcription programs, probably over several cell cycles.

Chromatin transcriptional signals are gene-specific. Specificity is established predominantly by enzymatic acetylation, methylation, phosphorylation, and ubiquitination of nucleosomal histones H2A/B, H3, and H4. Preferential sites for fine-tuning of transcriptional factor accessibility are lysine residues at defined positions 9, 88, 198, 199 on NH2-terminals of protruding histone tail domains 86, 95, 142, 200, 201. Phosphorylation of histone operates mostly in anaphase, apoptosis, DNA repair 145, 202 and in tumorigenesis [203] but is of lesser importance in this discussion. Chromatin-modifying enzymes are histone deacetylases (HDACs) 144, 203, 204, 205, acetyltransferases (HATs) [145] and methyltransferases (HMTs) 206, 207. HDACs exert major epigenomic transcription-repressing control functions on stabilization of DNA replication in collaboration with proliferating cell nuclear antigen and adenosine triphosphate–dependent complexes [52]. Repressing HDACs 93, 174, 208, 209 and transcription-promoting HATs [210] operate in shifting bidirectional equilibria, respectively, through transcription-inhibitory heterochromatin and transcription-permissive euchromatin. Gene replication modified by HDAC/HAT chromatin structurization also establish direct synergistic links to DNMT-mediated DNA transcription and thus stabilize E2F-targeted promotor- and tumor suppressor–genes. In fact, HDAC/HAT balances also affect auxiliary transcription-controller genes, such as telomere/telomerases, which, for example, in recollection of earlier memory information, supervise tumor suppressor genes and cycle arrest 58, 119, 120, 211, 212. Frequent pathogenetic constellations seen in neoplastic stem cells are inactivation of tumor suppressor genes by chromatin deacetylation (in particular of H3Lys9 and H4Lys16), deregulated histone acetylation 203, 204, 205 and methylation especially by MLL 165, 203, and concurrent disruption of the DNA methylation status by CpG hypermethylation/non-CpG hypomethylation of DNA promotor sequences 140, 143, 200, 213, 214. Not surprisingly, a wide range of synthetic HDAC transcription inhibitors are presently explored in clinical trials for their antineoplastic properties in attempts to restabilize epigenomic surveillance at G1 and G1/S, and to prevent transcription of abnormal genes 204, 215, 216, 217, 218, 219, 220, 221.

HATs, the opposing partners of HDACs in eu-/heterochromatic equilibria [164], provide access of transcription factors by decondensing regional chromatin and lysine-specific acetylation of H3/H4 histones 145, 210. HATs regulate levels of cyclin E/CDK2 complexes for cell entry of S-phase and trigger transcription of both proliferation- and differentiation-associated genes 9, 222, 223. HATs synergize with HMT-protein Ezh2 in antisenescent, proliferation-promoting and chromatin-remodeling effects on stem cells. Overexpression and aberrant acetylation by HATs of certain histone lysines operate as transcriptional cofactors for oncoproteins in the pathogenesis for some leukemias and solid tumors with a poor prognosis [224]. For example, in acute monocytic t(8;22)(p11;q13) leukemias, fusions of enzymes HAT-MOZ (monocytic leukemia zinc finger protein) and HAT-p300/CBP (CREB-binding protein) induce characteristic losses of histone acetylation and inhibition of cell differentiation 224, 225. On the other hand, HAT-p300/CBP enzymes may reinforce p53/p16 mediated tumor suppression 164, 204.

Methylation of chromatin-modifying enzymes is catalyzed by gene-specific HMTs 200, 206, 207, which either activate or repress gene transcription during G1-G1/S-processing depending on the position of lysines on histone molecules 141, 196, 197, 199, 207, 226, 227. HMTs include four MLL-H3Lys4 methyltransferases. MLLs complexes promote, coordinate and ensure proper cell cycle phase transitions and are of prime importance in the epigenomic “switch-on/off” control mechanisms of the cell cycle, but functional details are not fully understood 165, 203, 227. MLLs have C-terminal SET1 domains consisting of genes SUV39H1; Ezh1,2; and TRxG/PcG 197, 206, 207 that connect MLL to both, promotive and suppressive epigenomic regulators in mid- and late-phase G1 respectively 165, 228, 229, 230. MLLs engage in cross-talks with HATs [231], activate cyclin E/CDK2 complexes, mark CDKI p27 for degradation through phosphorylation, and have links to gene silencing by DNA-CpG methylation (via DNMTs) 163, 230. MLLs interact with tumor-suppressor Menin that promotes expression of CDKI p27Kip and p18INK4c [232]. In promotor genes lacking standard CpG islands [233], MLL-mediated gene silencing is accomplished by chromatin hypermethylation and upregulated polycomb transcription repressors 21, 52, 161. Deregulations of MLL genes are associated with clinically aggressive leukemic cell immortalization 203, 206, 229, 234, 235. MLL fusion proteins enforce high-level expression of genes HOX and HOAX co-factor MEIS1 which is pivotal for leukemigenesis [236]. In 10% of pediatric leukemias with 11q23 fusions, the DNA methylation status at chromosomal breakpoints is deregulated by HMT-mediated transcriptional repressors 161, 206, 237.

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DNA CpG and non- CpG methylation 

DNMT are transcription repressors of gene promotors. They catalyze DNA methylation through interaction with chromatin proteins TRxG/Ezh2 and, thus, are likely to also provide signals for processing of G1-G1/S cycle transitions 100, 102, 136, 230, 235. Indeed, DNMT1 regulates replication and maintenance of CpG-methylation patterns by repressing E2F1-responsive promotors through complex formation with pRb and HDAC1 181, 238. Its functions are repressed by losses or mutations of p53/pRb pathways, by overexpression of the p53-antagonist MDM2, or deregulation of CDKs and cycle arrest 26, 68, 135, 182, 188. DNMT3a,b affect the accessibility of transcription factors to genes and thus suppress gene transcription 40, 68, 81. They hypermethylate CpG islands including de novo methylation of premarked unmethylated CpG 57, 239, 240, 241 and hypomethylate non-CpG (i.e., CpA and CpT) sites 21, 25, 242, 243. In most human neoplasms, tumor suppressor genes are silenced by DNMT3a,b. This leads to transcriptional instability 244, 245, 246 (especially in aging cells in which abnormally methylated DNA sequences accumulate 81, 247, 248), and to expression of leukemia-associated oncogenes 25, 26, 105, 203, 249. Of pathogenetic importance is the association of abnormal DNA methylation with transcription repressor HDAC 144, 213, 244, with GATA-2-binding transcription factor PU.1 250, 251, and with regional communicative complexes to gene-specific heterochromatin 11, 38, 88, 201, 239, 247. Synthetic DNMT-inhibitors aim at selectively restoring activation of tumor suppressor functions by downregulating tumor-promotive cyclins, reactivating silenced CDKI, and dephosphorylating pRb [249].

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Hypothesis: Decision-making at the G1/S checkpoint—Epigenomic/genomic transcriptional instabilities of pre-/neoplastic stem cells 

Reorientation of transcriptional genomic programs by mitotic divisions (e.g. in switches from regular proliferation to differentiation/cycle arrest) requires epigenomically controlled decision-making for stabile DNA replication at the G1/S checkpoint, i.e. whether or not to allow a cell to enter S-phase 12, 13. Expression of neoplastic markers during aging processes of normal stem cells [30] suggests that genomic reorientation is associated with transcriptional instability. Although instabilities in regular switches appear to be momentary and are rapidly corrected to new stability levels, probably in G2/M phase, transcriptional genomic reorientation does entail the possibility of neoplastic transformation. Apparently the biology of transcriptional decision-making occasionally allows individual stem cells normally doomed for senescence, to avoid regular differentiation/apoptotic programs and instead divert to neoplastic proliferation (Fig. 3). In these instances, transcriptional epigenomic/genomic stability is not restored. Rather, abnormal neoplastic DNA replication due to deregulations and failure in scrutiny of the G1/S checkpoint directly activates CDKs [36] and repress CDK inhibitors 97, 161, 164, 252. In addition, chromatin-modifying enzymes HDAC/HAT/HMT-MLL 145, 205, 206, 213, 224, histone phosphorylation 145, 202, 203, PcG/TRxG/Ez2h 100, 102, 240, and DNMTs-mediated DNA methylation 240, 253, 254 also become involved in abnormal transcription. As a result, tumor suppressor proteins p15INK4B/p16INK4A are not activated, chromatin signaling does not allow access of differentiation-associated genes to S-phase for replication, and mutated genes are not silenced by de novo CpG hypermethylation 93, 240/non-CpG DNA hypomethylation 245, 246. In short, decision-making at the G1/S checkpoint is severely disturbed. However, it may not be completely abrogated 102, 161, 252 because transcriptional deregulations/instabilities in neoplastic transformation are nonrandom [255]. Rather, deregulations are tumor-specific involving entire sets of pathogenetic tumor-associated genes [29] in a wide spectrum of pre-/neoplastic human lesions 35, 147, 168. This agrees with concepts that each type of neoplasm has its own genomic transcription program [59].

Because epigenomic deregulation from chromatin-modifying enzymes and transcriptional instabilities during G1 interfere with regular G1/S decision-making in genomic reorientation programs of neoplasms, the possibility exists that developmentally silenced genes are activated for expression 243, 249, 251. These could even include components of the normal human genome that are nonhuman, infectious, and potentially tumorigenic DNA sequences. In this connection, it is important to remember that a sizable portion of the human genome normally is prevented from expression by silencing [256]. About half are mobile, transposable elements of nonhuman origin, transposons and retrotransposons, poorly characterized or even unidentified viral and parasitic DNA sequences 256, 257, 258. Retrotransposons, the most frequent variety, are capable of disrupting regular cell cycle proceedings, inhibit mRNA and protein expression, and even serve as fine-tuners for the human transcriptome. They establish new epigenomic balances and replicate in the host genome in response to telomeric erosion 259, 260, 261. To prevent transcription and clone formation of such potentially pathogenetic sequences, the human host regularly inactivates accumulating transposable elements by epigenomic silencing through DNA methylation 241, 257, 262, 263. In abnormal mitotic cycles with G1-G1/S deregulations, however, defense mechanisms will be severely disturbed. Of special concern are endogenous, vertebrate-specific retrovirus-like sequences (hERVs), which account for about 8% of the entire human genome [256]. hERV retroviruses are associated with human diseases, including neoplasms, but their infectivity and tumorigenicity in man has not been firmly established 264, 265, 266, 267, 268, 269. Thus, the possibility has not been excluded that they become activated during transcriptional reorientation/deregulation by reverse transcriptases and cause disease 270, 271, 272, 273.

Finally, it has been suggested that, in spite of uncoupling of proliferative from suppressive transcriptional pathways during tumorigenesis, “. . . the underlying tumour-suppressor programmes remain intact” [33]. If correct, therapeutic reactivation of tumor suppressor programs theoretically could coax neoplastic stem cells into transcriptional reorientation, i.e., to revert back to stabile senescent programs with innate mechanisms for physiological senescence, quasi as legacy of their former “friendly” behavior as physiological stem cells. Reorientation of entire transcription programs through epigenomic switches is, in fact, a not unusual biological phenomenon. It occurs in epithelial-mesenchymal transition 10, 23, 274, 275, in oncogene-induced expression of tumor suppressors 33, 192, 276, 277, in uncoupling of neoplastic transcription programs from apoptosis in mitotic spindle checkpoint abnormalities 27, 70, 72, 74, and in neoplastic transformation 25, 278. Numerous current pre-/clinical therapeutic trials with chromatin enzyme-modifying drugs 28, 204, 216, 279, 280, 281 address alterations in the CpG methylation status of aberrantly silenced genes [255], recoupling of proliferative with tumor suppressive pathways 21, 27, 282, 283, 284, and premarking for transcriptional repression by polycomb factors 103, 240.

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Conclusions and speculations 

Gene transcription and epigenomic control form a physiological entity that together governs the mitotic cell cycle. G1 phase and G1/S checkpoint are the final control points in gene reorientation programs before DNA replication, both regular and neoplastic, is implemented in S-phase: A wealth of incoming gene-specific information, mediated by precycle epigenomic chromatin arrangements and the DNA methylation status, is processed during G1 phase, which may vary considerably in duration. Indeed, transcriptional information is analyzed, selected, filtered, condensed, and then converged on the G1/S checkpoint for decision-making, i.e., whether the cell is admitted to S-phase for regular DNA replication, alternatively triggered into differentiation and/or cycle arrest or, occasionally, into neoplastic transformation (Fig. 2). Although little information exists on details of G1-G1/S processing for transcription of individual genes, it seems that epigenomic signals are transmitted from parental cells to their daughter cells for mitotic inheritance of genomic programs. This information may include neoplastic memory data. Of particular interest are questions why and how individual non- or preneoplastic daughter stem cells instead of undergoing senescence and/or cycle arrest, acquire neoplastic properties in genomic reorientation programs. A plausible explanation could be a failure of control functions of the G1/S checkpoint to exclude cells with transcriptional instabilities from DNA replication. But then, immediately, additional questions arise: By what mechanisms does G1/S decision-making fail? Or is it failure of signal processing and presentation during G1 passage? Is faulty decision-making of G1/S reversible at any point? We hypothesize that momentary transcriptional instabilities exist in genomic rearrangements during regular mitosis that are rapidly corrected to new levels of stability by epigenomic signals, probably during G2/M phase. In preneoplastic stem cells, however, abnormal transcriptional information transmitted by deregulated HDAC/HAT/HMT-MLL chromatin-modifying enzymes in combination with abnormal DNA methylation, are not corrected during signal processing in G1 phase. This leads to failure in G1/S decision-making, propagation of transcriptional instabilities, and replication of abnormal DNA sequences in S-phase (Fig. 3). It has recently been suggested that transcriptional instabilities in neoplastic transformation are tumor-specific involving entire sets of previously silenced pathogenetic genes so that eventually, during subsequent cell cycles, full neoplastic transformation is implemented. At this point it is worth remembering that the possibility has not been excluded that regular, but normally silenced components of the human genome, e.g., nonhuman infective and even potentially oncogenic genomic components such as hERV-Ks (endogenous retroviral) sequences, could be transcribed in abnormal DNA replication and cause disease.

In conclusion, we believe that abnormalities in processing of transcriptional information during G1 phase and/or failure of G1/S checkpoint of the mitotic cell cycle are the final, and possibly decisive steps that trigger neoplastic DNA transformation and replication of daughter stem cells. Thus, further studies of the dynamics of pre–S-phase processing of transcriptional information by the cell cycle will open up new therapeutic strategies.

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Acknowledgments 

There are no potential author conflicts of interest that relate to this manuscript.

We thank Drs. Robert J. Arceci, Baltimore, and Zina Ben-Ishay, Jerusalem, for valuable comments.

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References 

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–111
  2. Haan de G, Nijhof W, Zant van G. Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood. 1997;89:1543–1550
  3. Chen J, Astle CM, Harrison DE. Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp Hematol. 1999;27:928–935
  4. Marley SB, Lewis JL, Davidson RJ, et al. Evidence for a continuous decline in hematopoietic cell function from birth: application to evaluating bone marrow failure in children. Br J Haematol. 1999;106:162–166
  5. Zant van G, Liang Y. The role of stem cells in aging. Exp Hematol. 2003;31:659–672
  6. Liang Y, Zant van G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood. 2005;106:1479–1487
  7. Xing Z, Ryan MA, Daria D, et al. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006;108:2190–2197
  8. Colvin GA, Dooner MS, Dooner GJ, et al. Stem cell continuum: directed differentiation hotspots. Exp Hematol. 2007;35:96–107
  9. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3:662–673
  10. Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood. 2004;103:2892–2899
  11. Jepsen K, Rosenfeld MG. Biological roles and mechanistic actions of co-repressor complexes. J Cell Sci. 2002;115:689–698
  12. Kel-Margoulis OV, Tschekmenev D, Kel AE, et al. Composition-sensitive analysis of the human genome for regulatory signals. In Silico Biol. 2003;3:145–171
  13. Suzuki Y, Yamashita R, Shirota M, et al. Large-scale collection and characterization of promotors of human and mouse genes. In Silico Biol. 2004;4:429–444
  14. Campbell KHS, Loi P, Otaegui PJ, Wilmut I. Cell cycle co-ordination in embryo cloning by nuclear transfer. Rev Reprod. 1996;1:40–46
  15. Humpherys D, Eggan K, Akutsu H, et al. Epigenetic instability in ES cells and cloned mice. Science. 2001;293:95–97
  16. Wilmut I, Beaujean N, de Sousa PA, et al. Somatic cell nuclear transfer. Nature. 2002;419:583–586
  17. Tamada H, Kikyo N. Nuclear reprogramming in mammalian somatic cell nuclear cloning. Cytogenet Genome Res. 2004;105:285–291
  18. Dean W, Santos F, Reik W. Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. Semin Cell Develop Biol. 2003;14:93–100
  19. Niemann H, Tian XC, King WA, Lee RSF. Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning. Reproduction. 2008;135:151–163
  20. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3:895–902
  21. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692
  22. Hong D, Gupta R, Ancliff P, et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science. 2008;319(5861):336–339
  23. Prindull G. Hypothesis: cell plasticity, linking embryonal stem cells to adult stem cell reservoirs and metastatic cancer cells?. Exp Hematol. 2005;33:738–746
  24. Knudson AG. Mutation and cancer. Proc Natl Acad Sci U S A. 1971;68:820–823
  25. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21–33
  26. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643–649
  27. Dreesen O, Brivanlou AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev. 2007;3:7–17
  28. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457–463
  29. Edelman EJ, Guinney J, Chi JT, Febbo PG, Mukherjee S. Modeling cancer progression via pathway dependencies. PloS Comput Biol. 2008;4(2):e28
  30. Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102:9194–9199
  31. Bagnara GP, Bonsi L, Strippoli P, et al. Hematopoiesis in healthy old people and centenarians: well-maintained responsiveness of CD34+ cells to hematopoietic growth factors and remodeling of cytokine network. J Gerontol Biol Sci. 2000;55A:B61–B70
  32. Lundberg AS, Weinberg RA. Control of the cell cycle and apoptosis. Eur J Cancer. 1999;35:531–539
  33. Lowe SW, Cepero E, Evan G. Intrinsic tumor suppression. Nature. 2004;432:307–315
  34. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005;37:961–976
  35. Bartek J, Lukas J. DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol. 2007;19:238–245
  36. Shiloh Y. ATM and related protein kinases: safegurading genome integrity. Nat Rev Cancer. 2003;3:155–168
  37. Lieb JD, Beck S, Bulyk ML, et al. Applying whole-genome studies of epigenetic regulation to study human disease. Cytogenet Genome Res. 2006;114:1–15
  38. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet Suppl. 2003;33:245–254
  39. Cutfield WS, Hofman PL, Mitchell M, Morison IM. Could epigenetics play a role in the developmental origins of health and disease?. Pediatr Res. 2007;61:68R–75R
  40. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293:1089–1093
  41. Hasty P, Campisi J, Hoeijmakers J, Steeg van H, Vijg J. Aging and genome maintenance: lessons from the mouse?. Science. 2003;299:1355–1359
  42. Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990;301:1111
  43. Crews D, McLachlan JA. Epigenetics, evolution, endocrine disruption, health, and disease. Endocrinology. 2006;147(Suppl):S4–S10
  44. Coe CL, Lubach GR, Shirtcliff EA. Maternal stress during pregnancy predisposes for iron deficiency in infant monkeys impacting innate immunity. Pediatr Res. 2007;61:520–524
  45. Lanzuolo C, Orlando V. The function of the epigenome in cell reprogramming. Cell Mol Life Sci. 2007;64:1043–1062
  46. McEvoy TG, Ashworth CJ, Rooke JA, Sinclair KD. Consequences of manipulating gametes and embryos of ruminant species. Reprod Suppl. 2003;61:167–182
  47. Gao S, Latham KE. Maternal and environmental factors in early cloned embryo development. Cytogenet Genome Res. 2004;105:279–284
  48. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102:10604–10609
  49. Wong AHC, Gottesman IL, Petronis A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Human Mol Genet. 2005;14:R11–R18
  50. Petronis A. Epigenetics and twins: three variations on the theme. Trends Genet. 2006;22:347–350
  51. Bohr VA. DNA damage and its processing. Relation to human disease. J Inherit Metab Dis. 2002;25:215–222
  52. Berardi P, Russell M, El-Osta A, Riabowol K. Functional links between transcription, DNA repair and apoptosis. Cell Mol Life Sci. 2004;61:2173–2180
  53. Boer de J, Andressoo JO, Wit de J, et al. Premature aging in mice deficient in DNA repair and transcription. Science. 2002;296:1276–1279
  54. Syljuasen RG, Jensen S, Bartek J, Lukas J. Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polio-like kinase 1 kinases. Cancer Res. 2006;66:10253–10257
  55. Hutter G, Scheubner M, Zimmermann Y, et al. Differential effect of epigenetic alterations and genomic deletions of CDK inhibitors [p16(INK4a), p15(INK4b), p14(ARF)] in mantel cell lymphoma. Genes Chromosomes Cancer. 2006;45:203–210
  56. Herceg Z. Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis. 2007;22:91–103
  57. Baylin SB, Ohm JE. Epigenetic gene silencing in cancer—a mechanism for early pathway addiction. Nature Rev Cancer. 2006;6:107–116
  58. Jones PA. Overview of cancer epigenetics. Semin Hematol. 2005;42(Suppl):S3–S8
  59. Widschwendter M, Fiegl H, Egle D, et al. Epigenetic stem cell signature in cancer. Nat Genet. 2007;39:157–158
  60. Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet. 2004;38:413–443
  61. Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by polycomb in human embryonic stem cells. Cell. 2006;125:301–313
  62. Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006;20:1123–1136
  63. Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443:421–426
  64. Burdon T, Smith A, Savatier P. Signalling, cell cycle and pluripotency in embryonal stem cells. Trends Cell Biol. 2002;12:432–438
  65. Hardy K, Handyside AH, Winston RML. The human blastocyst: cell number, death and allocation during late preimplantation development in vitro. Development. 1989;107:597–604
  66. Jurisicova A, Rogers I, Fasciani A, Casper RF, Varmuza S. Effect of maternal age and conditions of fertilization on programmed cell death during murine preimplantation embryo development. Mol Hum Reprod. 1998;4:139–145
  67. Draper JS, Moore HD, Ruban LN, Gokhale PJ, Andrews PW. Culture and characterization of human embryonic stem cells. Stem Cells Dev. 2004;13:325–336
  68. Rhee I, Bachman KE, Park BH, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature. 2002;416:552–556
  69. Cui H, Cruz-Correa M, Giardiello FM, et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science. 2003;299:1753–1755
  70. Mantel C, Guo Y, Lee MR, et al. Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotypic instability. Blood. 2007;109:4518–4527
  71. Yu H. Regulation of APC-Cdc20 by the spindle checkpoint. Curr Opin Cell Biol. 2002;14:706–714
  72. Bharadwaj R, Yu H. The spindle checkpoint, aneuploidy, and cancer. Oncogene. 2004;23:2016–2927
  73. Kops GJPL, Foltz DR, Cleveland DW. Lethality to human cancer cells through masssive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci U S A. 2004;101:8699–8704
  74. Boyapati A, Yan M, Peterson LF, Biggs JR, LeBeau MM, Zhang DE. A leukemic fusion protein attenuates the spindle checkpoint and promotes aneuploidy. Blood. 2007;109:3963–3971
  75. Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of t(8;21) AML1-Eto translocations in childhood acute myeloid leukemia. Blood. 2002;99:3801–3805
  76. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history. Blood. 2003;102:2321–2333
  77. Scintu M, Vitale R, Prencipe M, et al. Genomic instability and increased expression of BUB1B and MAD2L1 genes in ductal breast carcinoma. Cancer Lett. 2007;254:298–307
  78. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21
  79. Kirkland MA, Quesenberry PJ, Roeder I. discrete stem cells: subsets or a continuum? [letter]. Blood. 2006;108:3949
  80. Paro R. Propagating memory of transcriptional states. Trends Genet. 1995;11:295–297
  81. Issa JP. Age-related epigenetic changes and the immune system. Clin Immunol. 2003;109:103–108
  82. Shen X, Xiao H, Ranallo R, Wu WH, Wu C. Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science. 2003;299:112–114
  83. Ling JQ, Hoffman AR. Epigenetics of long-range chromatin interactions. Pediatr Res. 2007;61:11R–16R
  84. Surani MA. Reprogramming of genome function through epigenetic inheritance. Nature. 2001;414:122–128
  85. Boyer LA, Lee TI, Cole MF, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005;122:947–956
  86. Cavalli G. Chromatin as a eukaryotic template of genetic information. Curr Opin Cell Biol. 2002;14:269–278
  87. Simon JA, Tamkun JW. Programming off and on states in chromatin: mechanisms of polycomb and thrithorax group complexes. Curr Opin Genet Dev. 2002;12:210–218
  88. Wolffe AP, Guschin D. Review: chromatin structural features and targets that regulate transcription. J Struct Biol. 2000;129:102–122
  89. Lund AH, Lohuizen van M. Polycomb complexes and silencing mechanisms. Curr Opin Cell Biol. 2004;16:239–246
  90. Erhardt S, Lyko F, Ainscough JFX, Surani MA, Paro R. Polycomb-group proteins are involved in silencing processes caused by a transgenic element from the murine imprinted H19/Igf2 region in Drosophila. Dev Genes Evol. 2003;213:336–344
  91. Trimarchi JM, Lees JA. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002;3:11–20
  92. Müller H, Bracken AP, Vernell R, et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 2001;15:267–285
  93. Henikoff S, Ahmad K. Assembly of variant histones into chromatin. Ann Rev Cell Dev Biol. 2005;21:133–153
  94. Hannon GJ. RNA interference. Nature. 2002;418:244–251
  95. Tomasi TB, Magner WJ, Khan ANH. Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immunother. 2006;55:1159–1184
  96. Kamminga LM, Bystrykh LV, Boer de A, et al. The polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood. 2006;107:2170–2179
  97. Reynolds PA, Sigaroudinia M, Zardo G, et al. Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem. 2006;281:24790–24802
  98. Tang X, Milyavsky M, Shats I, Erez N, Goldfinger N, Rotter V. Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene. 2004;23:5759–5769
  99. Pirrotta V. Chromatin complexes regulating gene expression in Drosophila. Curr Opin Genet Dev. 1995;5:466–472
  100. Viré E, Brenner C, Deplus R, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–874
  101. Voncken JW, Schweizer D, Aagaard L, Sattler L, Jantsch MF, Lohuizen van M. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J Cell Sci. 1999;112:4627–4639
  102. Caldas C, Aparicio S. Cell memory and cancer—the story of the trithorax and polycomb group genes. Cancer Metastasis Rev. 1999;18:313–329
  103. Piotrowski A. Genes Chromosomes Cancers. 2006;45:656–667
  104. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–822
  105. Valk-Lingbeek ME, Bruggeman SWM, Lohuizen van M. Stem cells and cancer: the polycomb connection. Cell. 2004;118:409–418
  106. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355:1253–1261
  107. Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992;89:10114–10118
  108. Khoo CM, Carrasco DR, Bodenberg MW, Paik JH, DePinho RA. Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomere-deficient mouse. Proc Natl Acad Sci U S A. 2007;104:3931–3936
  109. Campisi J, Kim S, Lim CS, Rubio M. Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol. 2001;36:1619–1637
  110. Hug N, Linger J. Telomere length homeostasis. Chromosoma. 2006;115:413–425
  111. Jacob NK, Lescasse RL, Linger BR, Price CM. Tetrahymena POT1a regulates telomere length and prevents activation of a cell cycle checkpoint. Mol Cell Biol. 2007;27:1592–1601
  112. Glover L, Alsford S, Beattie C, Horn D. Deletion of a trypanosome telomere leads to loss of silencing and progressive loss of terminal DNA in the absence of cell cycle arrest. Nucl Acids Res. 2007;35:872–880
  113. Itahana K, Campisi J, Dimri G. Mechanisms of cellular senescence in human and mouse cells. Biogerontology. 2004;5:1–10
  114. Johnson FB, Sinclair DA, Guarente L. Molecular biology of aging. Cell. 1999;96:291–302
  115. Multani AS, Chang S. WRN at telomeres: implications for aging and cancer. J Cell Sci. 2007;120:713–721
  116. Lange de T, Jacks T. For better or worse? Telomerase inhibition and cancer. Cell. 1999;98:273–275
  117. Caslini C, Hess JL. MLL modulates telomere length in mammalian cells. Blood. 2006;108(11, part 1):626a, Abstract 2209
  118. Yui J, Chiu CP, Lansdorp PM. Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood. 1998;91:3255–3262
  119. Serakinci N, Hoare SF, Kassem M, Atkinson SP, Keith WN. Telomerase promotor reprogramming and interaction with general transcription factors in the human mesenchymal stem cell. Regen Med. 2006;1:125–131
  120. Beliveau A, Bassett E, Lo AT, et al. p53-dependent integration of telomere and growth factor deprivation signals. Proc Natl Acad Sci U S A. 2007;104:4431–4436
  121. Beauséjour CM, Krtolica A, Galimi F, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003;22:4212–4222
  122. Holt SE, Glinsky VV, Ivanova AB, Glinsky GV. Resistance to apoptosis in human cells conferred by telomerase function and telomere stability. Mol Carcinog. 1999;25:241–248
  123. Maser RS, Wong KK, Sahin E, et al. DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol Cel Biol. 2007;27:2253–2265
  124. Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomerase loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–538
  125. Nguyen DC, Crowe DL. Intact functional domains of the retinoblastoma gene product (pRb) are required for downregulation of telomerase activity. Biochim Biophys Acta. 1999;1445:207–215
  126. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–198
  127. Reddel RR. The role of senescence and immortalization in carcinogenesis. Carcinogenesis. 2000;21:477–484
  128. Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet. 2001;28:155–159
  129. Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004;113:160–168
  130. González-Suárez E, Samper E, Flores JM, Blasco MA. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet. 2000;26:114–117
  131. Ji HJ, Rha SY, Jeung HC, Yang SH, An SW, Chung HC. Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss. Breast Cancer Res Treat. 2005;93:227–236
  132. Guittat L, Alberti P, Gomez D, et al. Targeting human telomerase for cancer therapeutics. Cytotechnology. 2004;45:75–90
  133. Thelen P, Wuttke W, Jarry H, Grzmil M, Ringert RH. Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J Urol. 2004;171:1934–1938
  134. Datta A, Bellon M, Sinha-Datta U, et al. Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence. Blood. 2006;108:1021–1029
  135. Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S. Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J. 2002;21:4183–4195
  136. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293:1068–1070
  137. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev. 1998;12:2245–2262
  138. Rashidian J, Iyirhiaro GO, Park DS. Cell cycle machinery and stroke. Biochim Biophys Acta. 2007;1772:484–493
  139. Bartek J, Lukas J. Order from destruction. Science. 2001;294:66–67
  140. Devaskar SU, Raychaudhuri S. Epigenetics—a science of heritable biological adaptation. Pediatr Res. 2007;61:1R–4R
  141. Fischle W, Wang Y, Allis CD. Histone and chromatin cross-talk. Curr Opin Cell Biol. 2003;15:172–183
  142. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–45
  143. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–1080
  144. Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte FJ. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann NY Acad Sci U S A. 2003;983:84–100
  145. Peterson CL, Laniel MA. Histones and histone modifications. Curr Biol. 2004;14:R546–R551
  146. Swat M, Kel A, Herzel H. Bifurcation analysis of the regulatory modules of the mammalian G1/S transition. Bioinformatics. 2004;20:1506–1511
  147. Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–870
  148. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512
  149. Sudarsanam P, Winston F. The Swi/Snf family: nucleosome-remodeling complexes and transcriptional control. Trends Genet. 2000;16:345–351
  150. Angelov D, Molla A, Perche PY, et al. The histone variant macroH2A interferes with transcription factor binding and SWI/SNF nucleosome remodeling. Mol Cell. 2003;11:1033–1041
  151. Kornberg RD. The eukaryotic gene transcription machinery. Biol Chem. 2001;382:1103–1107
  152. Bhalla KN. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol. 2005;23:3971–3993
  153. Saunders A, Core LJ, Lis JT. Breaking barriers to transcription elongation. Mol Cell Biol. 2006;7:557–567
  154. Liu H, Takeda S, Cheng EHY, Hsieh JD. Biphasic MLL takes helm at cell cycle control. Cell Cycle. 2008;7:428–435
  155. Sotillo E, Garriga J, Kurimchak A, Grana X. Cyclin E and SV40 Small t Antigen cooperates to bypass quiescence and contribute to transformation by activating CDK2 in human fibroblasts. J Biol Chem. 2008;283:11280–11292
  156. Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev. 2003;13:77–83
  157. Stein GH, Drullinger LF, Soulard A, Dulic V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 1999;19:2109–2117
  158. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A. 1996;93:13742–13747
  159. Sherr CJ. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol. 2001;2:731–737
  160. Bates S, Phillips AC, Clark PA, et al. p14ARF links the tumour suppressors RB and p53. Nature. 1998;395:124–125
  161. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83:993–1000
  162. Rowland BD, Denissov SG, Douma S, Stunnenberg HG, Bernards R, Peeper DS. E2F transcriptional repressor complexes are critical downstream targets of p19ARF/p53-induced proliferative arrest. Cancer Cell. 2002;2:55–65
  163. Carnero A, Hudson JD, Price CM, Beach DH. p16INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol. 2000;2:148–155
  164. Gonzalez-Paz N, Chng WJ, McClure RF, et al. Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications. Blood. 2007;109:1228–1232
  165. Dib A, Barlogie B, Shaughnessy JD, Kuehl WM. Methylation and expression of the p16INK4A tumor suppressor gene in multiple myeloma. Blood. 2007;109:1337–1338
  166. Hitomi T, Matsuzaki Y, Yasuda S, et al. Oct-1 is involved in the transcriptional repression of the p15INK4b gene. FEBS Lett. 2007;581:1087–1092
  167. Golubnitschaja O. Cell cycle checkpoints: the role and evaluation for early diagnosis of senescence, cardiovascular, cancer, and neurodegenerative diseases. Amino Acids. 2007;32:359–371
  168. Gorgoulis VG, Vassiliou LV, Karakaidos P, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434:907–913
  169. Sherr CJ. Cancer cell cycles. Science. 1996;274:1672–1677
  170. Azechi H, Nishida N, Fukuda Y, et al. Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas. Oncology. 2001;60:346–354
  171. Chen S, Chen L, Le NT, et al. Synthesis and activity of quinolinyl-methylene-thiazolinones as potent and selective cyclin-dependent kinase 1 inhibitors. Bioorgan Med Chem Lett. 2007;17:2134–2138
  172. Grillo M, Bott MJ, Khandke N, et al. Validation of cyclin D1/CDK4 as an anticancer drug target in MCF-7 breast cancer cells: effect of regulated overexpression of cyclin D1 and siRNA-mediated inhibition of endogenous cyclin D1 and CDK4 expression. Breast Cancer Res Treat. 2006;95:185–194
  173. Joshi KS, Rathos MJ, Joshi RD, et al. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol Cancer Ther. 2007;6:918–925
  174. Tagoh H, Melnik S, Lefevre P, Chong S, Riggs AD, Bonifer C. Dynamic reorganization of chromatin structure and selective DNA demethylation prior to stable enhancer complex formation during differentiation of primary hematopoietic cells in vitro. Blood. 2004;103:2950–2955
  175. Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF. Hypo-phosphorylation of the retinoblastoma protein (pRB) by cyclin D:Cdk4/6 complexes results in active pRb. Proc Natl Acad Sci U S A. 1997;94:10699–10704
  176. Knudsen KE, Weber E, Arden KC, Cavenee WK, Feramisco JR, Knudsen ES. The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death. Oncogene. 1999;18:5239–5245
  177. Lim IK. TIS21/BTG2/PC3 as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule. J Cancer Res Clin Oncol. 2006;132:417–426
  178. Lwin T, Hazlehurst LA, Dessureault S, et al. Cell adhesion induces p27Kip1-associated cell cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood. 2007;110:1631–1638
  179. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–707
  180. Narita M, Nunez S, Heard E, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113:703–716
  181. Imai MA, Oda Y, Oda M, Nakanishi I, Kawahara E. Overexpression of E2F1 associated with LOH at RB locus and hyperphosphorylation of RB in non-small cell lung carcinoma. J Cancer Res Clin Oncol. 2004;130:320–326
  182. Vousden KH. p53: death star. Cell. 2000;103:691–694
  183. Fan G, Ma X, Wong PY, Rodrigues CMP, Steer CJ. p53 dephosphorylation and p21Cip/Waf1 translocation correlate with caspase-3 activation in TGF-β1-induced apoptosis of HuH-7 cells. Apoptosis. 2004;9:211–221
  184. Khan SH, Moritsugu J, Wahl GM. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Proc Natl Acad Sci U S A. 2000;97:3266–3271
  185. Varela I, Cadinanos J, Pendás AM, et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature. 2005;437:564–568
  186. Ries S, Biederer C, Woods D, et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell. 2000;103:321–330
  187. Dumble M, Moore L, Chambers SM, et al. The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood. 2007;109:1736–1742
  188. Peterson EJ, Bögler O, Taylor SM. p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res. 2003;63:6579–6582
  189. Ren B, Cam H, Takahashi Y, et al. E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints. Genes Dev. 2002;16:245–256
  190. Rayman JB, Takahashi Y, Indjeian VB, et al. E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Genes Dev. 2002;16:933–947
  191. Stanelle J, Stiewe T, Theseling CC, Peter M, Pützer BM. Gene expression changes in response to E2F1 activation. Nucleic Acid Res. 2002;30:1859–1867
  192. Palmero I, Pantoja C, Serrano M. p19ARF links the tumour suppressor p53 to Ras. Nature. 1998;395:125–126
  193. Krishnamurthy J, Ramsey MR, Ligon KL, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443:453–457
  194. Molofsky AV, Slutsky SG, Joseph NM, et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during aging. Nature. 2006;443:448–452
  195. Frolov MV, Dyson NJ. Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci. 2004;117:2173–2181
  196. Bannister AJ, Schneider R, Kouzarides T. Histone methylation: dynamic or static?. Cell. 2002;109:801–806
  197. Rea S, Eisenhaber F, O'Carroll D, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000;406:593–599
  198. Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3:253–266
  199. Lachner M, Jenuwein T. The many faces of histone lysine methylation. Curr Opin Cell Biol. 2002;14:286–298
  200. Grewal SIS, Elgin SCR. Heterochromatin: new possibilities for the inheritance of structure. Curr Opin Genet Dev. 2002;12:178–187
  201. Bachman KE, Park BH, Rhee I, et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell. 2003;3:89–95
  202. Hendzel MJ, Wei Y, Mancini MA, et al. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentrometric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997;106:348–360
  203. Hake SB, Xiao A, Allis CD. Linking the epigenetic “language” of covalent histone modifications to cancer. Br J Cancer. 2004;90:761–769
  204. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24:1770–1783
  205. Senese S, Zaragoza K, Minardi S, et al. Role for histone deacetylase 1 in human tumor proliferation. Mol Cell Biol. 2007;27:4784–4795
  206. Schneider R, Bannister AJ, Kouzarides T. Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem Sci. 2002;27:396–402
  207. Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev. 2002;12:198–209
  208. Lee JH, Hart SRL, Skalnik DG. Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis. 2004;38:32–38
  209. Chang KT, Min KT. Regulation of lifespan by histone deacetylase. Ageing Res Rev. 2002;1:313–326
  210. Görisch SM, Wachsmuth M, Tóth KF, Lichter P, Rippe K. Histone acetylation increases chromatin accessibility. J Cell Sci. 2005;118:5825–5834
  211. Pandita TK, Hunt CR, Sharma GG, Yang Q. Regulation of telomere movement by telomere chromatin structure. Cell Mol Life Sci. 2007;64:131–138
  212. Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD, Hanson MA. Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res. 2007;61:5R–10R
  213. Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys 16 and trimethylation at Lys 20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005;37:391–400
  214. Pruitt K, Zinn RL, Ohm JE, et al. Inhibition of SIRT1 reactivates cancer silenced genes without loss of promotor DNA hypermethylation. PLoS Genet. 2006;2:e40
  215. Li H, Wu X. Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promotor in human cervical cancer cells. Biochem Biophys Res Com. 2004;324:860–867
  216. Schmidt M, Bastians H. Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug Resist Updat. 2007;10:162–181
  217. Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle. 2004;3:779–788
  218. Gojo I, Jiemjit A, Trepel JB, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood. 2007;109:2781–2790
  219. Vlasáková J, Nováková Z, Rossmeislová L, Kahle M, Hozák P, Hodný Z. Histone deacetylase inhibitors suppress IFNα–induced up-regulation of promyelocytic leukemia protein. Blood. 2007;109:1373–1380
  220. Florenes VA, Skrede M, Jorgensen K, Nesland JM. Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival. Melanoma Res. 2004;14:173–181
  221. Insinga A, Monestiroli S, Ronzoni S, et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med. 2005;11:71–76
  222. Zhang K, Williams KE, Huang L, et al. Histone acetylation and deacetylation: identification of acetylation and methylation sites of hela histone H4 by mass spectrometry. Mol Cell Proteomics. 2002;1:500–508
  223. Horn PJ, Peterson CL. Heterochromatin assembly: a new twist on an old model. Chromosome Res. 2006;14:83–94
  224. Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 2004;32:959–976
  225. Kitabayashi I, Aikawa Y, Yokoyama A, et al. Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. Leukemia. 2001;15:89–94
  226. Zhang Y, Reinberg D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 2001;15:2343–2360
  227. Fischle W, Wang Y, Jacobs SA, Kim Y, Allis CD, Khorasanizadeh S. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 2003;17:1870–1881
  228. Crawford BD, Hess JL. MLL core components give the green light to histone methylation. ACS Chem Biol. 2006;1:495–498
  229. Yokoyama A, Wang Z, Wysocka J, et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004;24:5639–5649
  230. Lee JH, Skalnik DG. CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set 1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex. J Biol Chem. 2005;280:41725–41731
  231. Dou Y, Milne TA, Tackett AJ, et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005;121:873–885
  232. Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci U S A. 2005;102:749–754
  233. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A. 2002;99:3740–3745
  234. Fröhling S, Scholl C, Bansal D, Huntly JP. HOX gene regulation in acute myeloid leukemia. Cell Cycle. 2007;6:2241–2245
  235. Ansari KI, Mishra BP, Mandal SS. Human CpG binding protein interacts with MLL1, MLL2 and hSet1 and regulates Hox gene expression. Biochim Biophys Acta. 2008;1779:66–73
  236. Caslini C, Yang Z, El-Osta M, Milne TA, Slany RK, Hess JL. Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res. 2007;67:7275–7283
  237. Daser A, Rabbitts TH. Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes Dev. 2004;18:965–974
  238. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promotors. Nat Genet. 2000;25:338–342
  239. Bachman KE, Rountree MR, Baylin SB. Dnmt3a and Dnmt3b are transcription repressors that exhibit unique locatization properties to heterochromatin. J Biol Chem. 2001;276:32282–32287
  240. Schlesinger Y, Straussman R, Keshet I, et al. Polycomb-mediated methylation of Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007;39:232–236
  241. Fazzari MJ, Greally JM. Epigenomics: beyond CpG islands. Nat Rev Genet. 2004;5:446–455
  242. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A. 2000;97:5237–5242
  243. Esteller M, Herman JG. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol. 2002;196:1–7
  244. Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J. 2001;20:2536–2544
  245. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003;300:455
  246. Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomic hypomethylation. Science. 2003;300:489–492
  247. Richardson B. Impact of aging on DNA methylation. Ageing Res Rev. 2003;2:245–261
  248. Singhal RP, Mays-Hoopes LL, Eichhorn GL. DNA methylation in aging of mice. Mech Ageing Dev. 1987;41:199–210
  249. Herman JG, Baylin SB. Gene silencing in cancer in association with promotor hypermethylation. N Engl J Med. 2003;349:2042–2054
  250. Kitajima K, Tanaka M, Zheng J, et al. Redirecting differentiation of hematopoietic progenitors by a transcription factor, GATA-2. Blood. 2006;107:1857–1863
  251. Suzuki M, Yamada T, Kihara-Negishi F, et al. Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b. Oncogene. 2005;25:2477–2488
  252. Herman JG, Civin CI, Issa JPJ, Collector MI, Sharkis SJ, Baylin SB. Distinct pattern of p15INK4A and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 1997;57:837–841
  253. EL-Osta A. DNMT cooperativity—the developing links between methylation, chromatin structure and cancer. Bioessays. 2003;25:1071–1084
  254. Agrawal S, Hofmann WK, Tidow N, et al. The C/EBPδ tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood. 2007;109:3985–3905
  255. Costello JF, Frühwald MC, Smiraglia DJ, et al. Aberrant CpG-island methylation has non-random and tumor-type-specific patterns. Nat Genet. 2000;24:132–138
  256. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921
  257. Lippman Z, Gendrel AV, Black M, et al. Role of transposable elements in heterochromatin and epigenetic control. Nature. 2004;430:471–476
  258. Kazazian HH. Mobile elements: driver of genome evolution. Science. 2004;303:1626–1632
  259. Capy P, Gasperi G, Biémont C, Bazin C. Stress and transposable elements: co-evolution or useful parasites?. Heredity. 2000;85:101–106
  260. Scholes DT, Kenny AE, Gamache ER, Mou Z, Curcio MJ. Activation of a LTR-retrotransposon by telomere erosion. Proc Natl Acad Sci U S A. 2003;100:15736–15741
  261. Han JS, Szak ST, Boeke JD. Transcriptional disruption by L1 retrotransposon and implications for mammalian transcriptomes. Nature. 2004;429:268–274
  262. Cheng C, Daigen M, Hirochika H. Epigenetic regulation of the rice retrotransposon Tos17. Mol Gen Genomics. 2006;276:378–390
  263. Liu ZL, Han FP, Tan M, et al. Activation of a rice endogenous retrotransposon Tos17 in tissue culture is accompanied by cytosine demethylation and causes heritable alteration in methylation pattern of flanking genomic regions. Theor Appl Genet. 2004;109:200–209
  264. Denne M, Sauter M, Armbruester V, Licht JD, Roemer K, Mueller-Lantzsch N. Physical and functional interactions of human endogenous retrovirus proteins Np9 and Rec with the promyelocytic leukemia zinc finger protein. J Virol. 2007;81:5607–5616
  265. Parseval de N, Heidmann T. Human endogenous retroviruses: from infectious elements to human genes. Cytogenet Genome Res. 2005;110:318–332
  266. Wang-Johanning F, Liu J, Rycaj K, et al. Expression of multiple human endogenous retrovirus surface envelope proteins in ovarian cancer. Int J Cancer. 2006;120:81–90
  267. Lewitzky M, Yamanaka S. Reprogramming somatic cells towards pluripotency by defined factors. Curr Opin Biotechnol. 2007;18:467–473
  268. Nelson PN, Carnegie PR, Martin J, et al. Demystified human endogenous retroviruses. J Clin Pathol Mol Pathol. 2003;56:11–18
  269. Büscher K, Trefzer U, Hofmann M, Sterry W, Kurth R, Denner J. Expression of human endogenous retrovirus K in melanomas and melanoma cell lines. Cancer Res. 2005;65:4172–4180
  270. Griffiths DJ. Endogenous retroviruses in the human genome sequence. Genome Biol. 2001;2:1017.1–1017.5reviews
  271. Moyes D, Griffiths DJ, Venables PJ. Insertional polymorphisms: a new lease of life for endogenous retroviruses in human disease. Trends Genet. 2007;23:326–333
  272. Bannert N, Kurth R. Retroelements and the human genome: new perspectives on an old relation. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14572–14579
  273. Gifford R, Tristem M. The evolution, distribution and diversity of endogenous retroviruses. Virus Genes. 2003;26:3,291–3,315
  274. Prindull GA, Fibach E. Are postnatal hemangioblasts generated by dedifferentiation from committed hematopoietic stem cells?. Exp Hematol. 2007;35:691–701
  275. Perez-Pomares JM, Munoz-Chapuli E. Epithelial-mesenchymal transitions: a mesodermal cell strategy for evolutive innovation in metazoans. Anat Rec. 2002;268:343–351
  276. Duelli DM, Lazebnik YA. Primary cells suppress oncogene-dependent apoptosis. Nat Cell Biol. 2000;2:859–862
  277. Malumbres M, Pérez De Castro I, Hernández MI, Jiménez M, Corral T, Pellicer A. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15INK4b. Mol Cell Biol. 2000;20:2915–2925
  278. Lotem J, Sachs L. Epigenetics wins over genetics: induction of differentiation in tumor cells. Semin Cancer Biol. 2002;12:339–346
  279. Araki H, Yoshinaga K, Boccuni P, Zhao Y, Hoffman R, Mahmud N. Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulation potential. Blood. 2007;109:3570–3578
  280. Lavelle D, Vaitkus K, Hankewych M, Singh M, DeSimone J. Effect of 5-ara-2′-deoxycytidine (Dacogen) on covalent histone modifications of chromatin associated with the ε-, γ-, and β-globin promoters in Papio anubis. Exp Hematol. 2006;34:339–347
  281. Waggoner D. Mechanisms of disease: epigenesis. Semin Pediatr Neurol. 2007;14:7–14
  282. Huntly BJP, Gilliland DG. Summing up cancer stem cells. Nature. 2005;435:1169–1170
  283. Jones RJ, Matsui WH, Smith BD. Cancer stem cells: are we missing the target?. J Nat Cancer Inst. 2004;96:583–585
  284. Huff CA, Matsui W, Smith BD, Jones RJ. The paradox of response and survival in cancer therapeutics. Blood. 2006;107:431–434

PII: S0301-472X(08)00374-3

doi:10.1016/j.exphem.2008.07.009

Experimental Hematology
Volume 36, Issue 11 , Pages 1403-1416, November 2008

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