Bookmarking Target Genes in Mitosis: a Shared Epigenetic Trait of Phenotypic Transcription Factors and Oncogenes?

Published OnlineFirst January 9, 2014; DOI: 10.1158/0008-5472.CAN-13-2837

Cancer Review Research

Bookmarking Target Genes in Mitosis: A Shared Epigenetic Trait of Phenotypic Transcription Factors and Oncogenes?

Sayyed K. Zaidi1,2, Rodrigo A. Grandy1,2, Cesar Lopez-Camacho1,2, Martin Montecino3,4, Andre J. van Wijnen5,6, Jane B. Lian1,2, Janet L. Stein1,2, and Gary S. Stein1,2

Abstract The regulatory information for phenotype, proliferation, and growth of normal and tumor cells must be maintained through genome replication in the S phase and cell division during mitosis. Epigenetic mechanisms that include DNA methylation, posttranslational modiﬁcations of histones, selective utilization of histone variants, and inheritable RNA molecules play pivotal roles in maintaining cellular identity through mitotic divisions. Recent studies demonstrate that mitotic occupancy of genes, which are determinants of cell fate, growth, and proliferation, by lineage-restricted transcription factors is a key epigenetic mechanism for retention and transmission of cellular expression memory. Evidence is emerging for the presence of distinct transcriptional regulatory microenvironments in mitotic chromosomes in which the genes bookmarked for reactivation postmitotically reside. Importantly, some oncoproteins are present in mitotic microenvironments where they occupy target genes during mitosis and may contribute to perpetuating the transformed phenotype. We discuss emerging regulatory implications of epigenetically bookmarking genes during mitosis for physiologic control as well as for the onset and progression of cancer. Cancer Res; 74(2); 1–6. 2014 AACR.

Introduction on mitotic bookmarking of genes by transcription factors as Mitosis, the process of cell division, poses a challenge to an emerging epigenetic mechanism that sustains cellular maintain cellular identity. In normal diploid cells, lineage- memory. As discussed later in this review, much of our current restricted transcription must resume in an efficient and faith- understanding of the mitotic gene bookmarking stems from ful manner following mitosis. In tumor and transformed cells, studies carried out in cell differentiation and proliferation there is an equivalently stringent requirement to sustain the models. We present the case that a similar bookmarking cancer phenotype through successive cell divisions. Genetic mechanism may be operative in the onset, progression, and information plays a key role in maintaining cellular identity, maintenance of cancer phenotype. but it is becoming increasingly evident that epigenetic mechanisms are pivotal to sustaining cellular memory. Studies Mitotic Chromosomal Microenvironment over the past decade have provided insights into epigenetic Chromatin reconfiguration during replication and mitosis mechanisms that maintain cellular identity in lineage-com- poses a major regulatory challenge for cells to perpetuate mitted as well as in cancer cells. Mitotically heritable post- identity as well as transcriptional regulatory commitment translational modifications and stoichiometry among variants through architectural remodeling that includes chromatin of histone proteins, as well as methylation of CpG islands unfolding, replication, condensation, and segregation. Com- present in DNA-regulatory elements of developmental, phe- pared with replication, chromatin undergoes striking struc- notypic, and cancer-related genes, are key in marking genes for tural and physical changes during mitosis; the 10-nm nucle- reactivation immediately after cell division. These epigenetic osomal fiber condenses more than 70-fold to configure mitotic mechanisms and their roles in heritable cellular memory are chromosomes (5). The highly compacted chromatin organi- well established and have been reviewed (1–4). Here, we focus zation of mitotic chromosomes, combined with historically significant observations from pulse-chase radiolabeling Authors' Affiliations: 1Vermont Cancer Center, College of Medicine; approaches, suggested that transcription is universally inhib- 2Department of Biochemistry, University of Vermont, Burlington, Vermont; 3Center for Biomedical Research; 4FONDAP Center for Genome Regula- ited during mitosis, and that the condensed chromosomes are tion, Universidad Andres Bello, Santiago, Chile; Departments of 5Ortho- not readily accessible to nuclear proteins (6, 7). Subsequently, 6 pedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, experiments carried out on pure mitotic cell populations Rochester, Minnesota demonstrated selective nuclease accessibility of mitotic chro- Corresponding Authors: Gary S. Stein and Sayyed K. Zaidi, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405. Phone: 802- mosomes, suggesting that components of the mitotic chro- 656-6613; Fax: 802-656-6613; E-mail: [email protected] and matin may not be transcriptionally inert (8). Ligation-mediated [email protected] PCR (LM-PCR) studies of specific gene promoters during doi: 10.1158/0008-5472.CAN-13-2837 mitosis further corroborated the observation that regions 2014 American Association for Cancer Research. within mitotic chromosomes are accessible to regulatory

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TSS Nucleosome

H3.3 containing nucleosomes H2A.Z containing nucleosome

Coregulatory CDproteins Lineage-specific TF binding Cohesin transcription factor cluster

Transcription factor binding site

Figure 1. Distinct epigenetic regulatory microenvironments for gene bookmarking that are present in mitotic chromosomes. Emerging evidence suggests that mitotic chromosomes exhibit a distinct epigenetic regulatory microenvironment where various mechanisms of gene bookmarking are operative. These include incorporation of histone H3.3 variant into genes that are bookmarked for reactivation postmitotically (A), incorporation of histone H2A.Z into nucleosome closer to transcription start sites (TSS) and its sliding on to TSS before mitosis for postmitotic expression (B), maintenance of nuclease accessible regions by cohesin where transcription factors are recruited after cell division (C), and target gene occupancy by sequence transcription factors for postmitotic gene activation (D). These microenvironments are not mutually exclusive and may function in concert with other epigenetic mechanisms (e.g., DNA methylation) for maintenance of cellular potential for lineage commitment, growth, and proliferation or even disease initiation, progression, and perpetuation.

proteins (9). Evidence is emerging for specific regulatory in regulatory elements of target genes. The Runx (AML/Cbfa) microenvironments present in mitotic chromosomes where family of transcription factors is an initial example of mitot- genes involved in biologic control and cancer are bookmarked ically retained nuclear regulatory proteins (11). Runx factors for rapid reactivation postmitotically (Fig. 1). share a highly conserved DNA-binding domain (designated Runt homology domain for its homology to the Drosophila Properties of nuclear proteins that bookmark genes in Runt protein) and exhibit recognition of a unique DNA-binding mitosis motif within the regulatory regions of target genes (12). Recent advances in high-resolution microscopy as well as Recently, it has been shown that the liver-related transcription genome-wide biochemical approaches (e.g., chromatin immu- factor FoxA1 and the hematopoietic regulator GATA1 are noprecipitation followed by high-throughput sequencing) have among many transcription factors that bind to lineage-restrict- provided an unbiased and comprehensive assessment of tran- ed target genes during mitosis (13, 14). These sequence-specific scriptional dynamics in mitotic cells. Accruing evidence from interactions mediate postmitotic reactivation of their respec- studies in a variety of lineages suggests that transcription tive differentiation programs. With few exceptions (15, 16), factors that play essential roles in conferring lineage identity most mitotically retained proteins exhibit sequence-specific often remain associated with target genes on mitotic chromo- recognition of regulatory DNA elements in target genes, indi- somes. The evidence is limited but compelling. Here, we outline cating that sequence specificity is an important property of some of the general properties of nuclear proteins that are nuclear regulatory proteins that remain associated with mitot- retained with target genes during mitosis: ic chromosomes. Sequence specificity. Although it has been shown that Scaffolding proteins. Another shared property of tran- many sequence-specific transcription factors are displaced scription factors that bookmark target genes during mitosis from condensed chromosomes during mitosis (10), several is that these proteins reside in specific nuclear microenvir- functionally significant nuclear proteins remain associated onments in the interphase nucleus and assemble multi- with mitotic chromosomes. Mitotically retained nuclear pro- protein regulatory complexes at strategic sites of target teins include components of basal transcription machinery, gene promoters that often contain chromatin remodeling coregulatory proteins that include activators, suppressors, and factors, coactivators, and cosuppressors (17). To what extent chromatin remodeling factors, as well as lineage-restricted the cohort of coregulatory proteins is retained on mitotic transcription factors that interact with cognate binding motifs chromosomes with the scaffolding proteins remains to be

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determined. Experimental evidence is provided by the Runx2 ing mitosis. However, use of GFP for live-cell microscopy transcription factor. Runx2 coordinates cell proliferation, requires the expression of artificially constructed transgenes growth, and differentiation by regulating both the RNA Pol I ectopically expressed in cells above physiologic levels. It and RNA Pol II genes (18, 19). During mitosis, Runx2 remains to be established whether the endogenous proteins selectively occupies target genes regulated by RNA Pol II, under physiologic conditions follow similar kinetics. Addition- as well as the RNA Pol I rRNA genes. Biochemical and in situ al considerations include quantitative determination of tran- studies reveal that Runx2 remains associated with TLE2, a scription factor concentration/association/dissociation anal- cosuppressor of Runx target genes, but dissociates from yses and mobility of proteins involved in epigenetic HDAC1, another coregulator (20). Additional examples of bookmarking. coregulatory proteins without known DNA-binding activity include bromodomain containing BRD proteins that recog- Properties of genes that are bookmarked in mitosis nize acetylated histones and remain associated with mitotic As discussed earlier in this review, for decades, it had been chromosomes (15, 16, 21). Global proteomics and multiplex assumed that highly compact and condensed mitotic chro- in situ studies are warranted to further explore the complete mosomes are not accessible to nonhistone proteins to the cohort of coregulators that remain associated with mitoti- chromatin. It has, however, become increasingly evident that cally retained transcription factors. despite compaction, some regions of the mitotic chromo- Lineage master regulators. Most of the transcription somesremaininanopenconformationandaccessibleto factors that bookmark target genes during mitosis are also regulatory proteins and that the mitotically bookmarked master regulators of respective lineages. For example, GATA1, genes share several properties: which remains associated with target genes during mitosis for Nuclease accessible. In the mid-1970s, pulse-chase radi- their reactivation after cell division, is a master regulator that olabeling experiments on mitotic chromosomes of the kan- controls erythroid lineage differentiation from hematopoietic garoo rat revealed that the compacted mitotic chromosomes stem cells (13, 22). Similarly, FoxA1 regulates specification of were indeed amenable to nuclease digestion (8). Subsequent liver cell differentiation (14, 23). Other examples include Runx studies using LM-PCR identified several genes, including factors that regulate the hematopoietic (Runx1), osteogenic Hsp70 and Myc among others that were accessible to nucle- (Runx2), and gastrointestinal/neurogenic (Runx3) lineages, the ase and were occupied by regulatory proteins (32). For key adipogenic regulator C/EBPa, and MyoD, the master example, the Myc gene, which is repressed during mitosis, regulator of muscle differentiation (11, 12, 18, 24–29). These is rapidly reactivated after cells divide. Many sequence- observations raise an interesting possibility that lineage iden- specific proteins that recognize and bind to single-stranded tity is, in part, sustained by mitotic gene bookmarking. Addi- DNA (e.g., hnRNP K and FBP) regulate Myc gene transcriptional studies are required to establish whether mitotic book- tion. Interestingly, several genes that are rapidly reactivated marking of genes is a common property of all lineage-deter- after mitosis are selectively sensitive to permanganate only mining transcription factors. during mitosis, but not in other stages of the cell cycle. These Dynamics of mitotic bookmarking. It is becoming observations indicate a unique and selective behavior of increasingly evident that mitotic bookmarking of target genes bookmarked genes during mitosis, in which they are acces- for rapid activation is a shared property of phenotypic tran- sible to single-strand DNA-binding proteins for rapid reac- scription factors. However, the mechanistic underpinnings of tivation postmitotically. Genome-wide studies are required the process remain underexplored. Insights into the process to assess whether nuclease accessibility is a common feature have been provided by live-cell imaging experiments that of all mitotically bookmarked genes. combined the power of live cell microscopy and fluorescence Enrichment of selective histone modifications and/or recovery after bleach to establish kinetics of gene reactivation histone variants H2A.Z and H3.3 in gene promoters. There postmitotically (21, 30, 31). For example, Prasanth and collea- is emerging evidence that the nucleosomes of bookmarked gues have shown that specific gene loci that are active before genes are enriched in histone variants, particularly in H2A.Z mitosis exhibit increased kinetics of activation in postmitotic and H3.3. Ng and Gurdon have shown that the memory for cells (31). Recruitment kinetics for the RNA Pol II and chro- the myogenic gene MyoD expression, in which histone H3.3 matin modifier BRD4 are different in interphase and mitotic has been incorporated into the nucleosomes, can persist cells. Mechanistically, enhanced BRD4 recruitment results through 24 cell divisions in the absence of transcription from increased levels of H4K5Ac on the previously activated (33). Mechanistically, the association of a mutated histone locus. BRD4 accelerated the dynamics of mRNA synthesis by H3.3, which lacks the methylatable H3.3 lysine 4, with promoter decompacting chromatin and hence facilitating transcription- DNA eliminates memory, indicating a requirement of H3.3 K4 al reactivation. Previous studies showed that components of for memory (33). An alternate mechanism of gene bookmark- the transcriptional regulatory and RNA-processing machiner- ing by histone variants is provided by genome-wide association ies sequentially enter the telophase nuclei after the nuclear of H2A.Z (34). Kelly and colleagues have shown that in active envelope is re-formed (31). These studies reveal that genes gene promoters þ1, nucleosomes [immediately downstream activated before mitosis are marked for rapid reactivation of the transcription start sites (TSS)] containing H2A.Z shift following mitosis, and the machinery is assembled in situ to upstream to occupy TSSs during mitosis, significantly reducing resume transcription immediately after cell division (30). Such nucleosome-depleted regions (34). This change seems to be single-cell studies elucidate kinetics of gene activation follow- specific to active genes that are silenced during mitosis and

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rapidly reactivated postmitotically (e.g., GRP78 gene). Impor- Implications of Mitotic Gene Bookmarking tantly, these authors find that trimethylation of lysine 4 at Sustained lineage identity histone H3 (H3K4me3) is also maintained enriched at these In committed cells, lineage identity must be sustained as promoters during mitosis, whereas other epigenetic markers of cells replicate and equally distribute genetic information to active chromatin are lost. progeny. Mitotic gene bookmarking by transcription factors, in Histone modifications play a key role in epigenetically combination with DNA methylation and histone modifications regulating gene expression in the interphase cells and their as well as selective incorporation of histone variants in the role in bookmarking genes during mitosis has been well chromatin of bookmarked genes, provides a mechanistic basis studied (1). Additional evidence for a role of histone modifica- for sustained lineage identity through cell divisions. Studies tions in mitotic gene bookmarking is suggested by observa- over the past decade have demonstrated that several pheno- tions at the level of a higher-order chromosome architecture typic transcription factors remain associated with target genes (35). In this study, Terrenoire and colleagues have found a during mitosis for rapid transcriptional control postmitoti- striking similarity in the distribution patterns of histone cally. So far, more than 15 transcription factors including many H3K4me3 between interphase and metaphase cells. It is nota- lineage-determining factors have been reported to be associ- ble that the methylation of histone H3 at lysine 4, in combi- ated with mitotic chromosomes (39). Examples include the nation with histone H2A.Z variant, provides a mark for acti- basic helix–loop–helix myogenic regulatory factors in muscle vation-associated acetylation of genes in the interphase (36). cell differentiation, CCAAT/enhancer-binding protein a in the Although it remains to be investigated whether a gene that is adipocyte differentiation program, FoxA1 in liver cells, GATA1 active in G2 cells is selectively marked during mitosis via and Runx1 in hematopoietic lineage differentiation, and Runx2 H3K4me3 modification, and is acetylated before reactivation in osteoblast differentiation (11, 13, 14, 24, 25, 27). Frequently, fi in G1 cells, these observations suggest that a mitosis-speci c these phenotypic transcription factors associate with selected histone code may, in part, orchestrate gene bookmarking. target genes involved in cell growth, proliferation, and differ- Together, these observations indicate that various chromatin entiation, thus coordinating maintenance not only of lineage marks that include selective incorporation of histone variants identity but also cellular potential for a physiologic balance and retention of specific epigenetic posttranslational modifi- between growth and proliferation. Despite the growing list of cations contribute to mitotic gene bookmarking. mitotically retained transcription factors, our current under- Demarking by cohesin. Is bookmarking of genes during standing for functional role(s) of mitotic gene bookmarking mitosis a universal phenomenon? It is unclear, and unlikely, remains minimal. For example, it is not clear if mitotic occu- that all genes that are rapidly reactivated postmitotically are pancy of a target gene by the transcription factor is a prereq- occupied by transcription factors during mitosis. In fact, it has uisite for reactivation postmitotically. Furthermore, are all been shown that many sequence-specific transcription factors mitotically retained transcription factors functional immedi- are selectively displaced from mitotic chromosomes (10). Dis- ately after mitosis or is the mitotic retention merely a mech- placement of transcription factors from mitotic chromosomes anism to equally distribute regulatory proteins to progeny indicates the presence of additional epigenetic mechanisms that cells? Genome-wide experimental approaches involving do not involve occupancy of target genes by transcription factors. endogenous transcription factors in biologically relevant sys- Recently, genome-wide chromatin immunoprecipitation studies tems will provide mechanistic insights into functional rele- followed by high-throughput sequencing have revealed binding vance of mitotic gene bookmarking in maintaining epigenetic patterns for hundreds of transcription factors (37). These studies cell memory in progeny cells. show that bound transcription factors are highly clustered and that these clusters are enriched in binding motifs for several Maintenance of stem-cell niches major transcription factor classes. Strikingly, most clusters are It is hypothesized that, in contrast with embryonic stem formed around cohesin, a protein required for chromosome cells, adult stem cells undergo at least one round of asym- condensation during mitosis (38). Mechanistically, cohesin plays metric cell division to generate lineage-committed cells and two key roles: During the S phase of the cell cycle, it holds the maintainthestem-cellpool.Wehavediscussedrecent replicating strands together at the transcription factor cluster observations that lineage-determining transcription factors sites, and during mitosis, it remains bound to the clusters even associate with target genes during symmetrical cell division when the transcription factors have been displaced from target to maintain cellular identity. We suggest a requirement for genes. Functionally, loss of cohesin decreases both DNA acces- asymmetric bookmarking of target genes in lineage-com- sibility and binding of transcription factors to clusters. These mitted stem cells by phenotypic transcription factors or by results provide a mechanistic explanation of a decades-long oncogenes in cancer stem cells to generate committed or observation that mitotic chromosomes are nuclease accessible transformed cells. Despite broad-based relevance, asymmet- (8). Furthermore, these observations suggest that cohesin bind- ric cell division has been predominantly studied in yeast or ing promotes reestablishment of transcription factor clusters Drosophila. For example, in budding yeast, the Ace2 chro- and reactivation of target genes after DNA replication as well as matin-remodeling factor is asymmetrically accumulated in after mitosis, thus providing a secondary mechanism for main- the nucleus of the daughter cell, perhaps regulating gene taining cellular memory through cell divisions. expression that is restricted to the progeny cell (40). During Drosophila neurogenesis, Numb, an attenuator of Notch signaling, and the Prospero transcription factor are

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selectively distributed to progeny cells as a mechanism to Concluding Remarks maintain the stem-cell population and to give rise to com- Mitotic bookmarking of target genes by sequence-specific mitted cells (41). Similar mechanisms may be operative in transcription factors is emerging as a frequently invoked mammalian cells. In fact, there is compelling evidence for epigenetic mechanism to sustain lineage identity in normal asymmetric orientation of the mitotic spindle in gut epi- cells and to perpetuate the transformed phenotype. Further thelium as well as in muscle stem cells that dictates lineage insights into mechanistically understanding bookmarking commitment as well as maintenance of the stem-cell pool requires addressing questions such as the following: (i) Is – (42 44). However, experimental evidence and a model sys- mitotic retention of regulatory proteins a transcriptional reg- tem to establish the existence of asymmetrical mitotic gene ulatory mechanism to reactivate gene expression postmitoti- bookmarking in mammals are lacking. To which extent cally, or do some mitotically retained proteins merely use cancer stem cells undergo asymmetric and/or symmetric dividing chromosomes as vehicles for equal distribution into cell division remains open ended and clinically and biolog- progeny cells? (ii) Do signaling pathways operative before ically relevant. This may have important implications for mitosis dictate which genes will be bookmarked? (iii) What developing therapeutic strategies that target the persistent are the dynamics of coregulatory protein complex organization tumorprogenitorpooloractivelydividingtumorcellsthat and activity during mitosis? (iv) Does the cohort of coregula- have escaped from the cancer stem-cell niche. Despite tory factors that remain associated with transcription factors current experimental limitations, epigenetic bookmarking define the postmitotic transcriptional status of bookmarked fl – fi provides a exible, yet cell type speci c and context-depen- genes? (v) Does colocalization of genes in the chromatin dent mechanistic dimension to gene regulation. microenvironment contribute to mitotic gene bookmarking? and (vi) Can the accumulation of transcription factors on Propagation of disease phenotype mitotic chromosomes be therapeutically targeted in dividing Evidence is accruing that mitotic gene bookmarking may cells? Additional studies will be necessary to further elucidate a have an important role in the onset, progression, and functional link between mitotic gene bookmarking and main- perpetuation of disease. This is illustrated by the leukemic tenance of cellular memory within the context of biologic fusion protein AML1-ETO that blocks myeloid differentia- control and pathology of cancer. tion and enhances proliferative potential (27). Interestingly, mitotic association of the leukemic AML1-ETO with the Disclosure of Potential Conflicts of Interest rRNA genes, as well as with genes controlling cell prolifer- No potential conflicts of interest were disclosed. ation and myeloid cell differentiation, upregulates rRNA and cell proliferation-related genes, but downregulates gene Authors' Contributions mediating myeloid cell differentiation, promoting and/or Conception and design: S.K. Zaidi, M. Montecino, A. van Wijnen, J.B. Lian, G.S. supporting transformed phenotype. Another recent exam- Stein Analysis and interpretation of data (e.g., statistical analysis, biostatistics, ple of cancer-related mitotic gene bookmarking is the computational analysis): A. van Wijnen mixed lineage leukemia (MLL) protein. MLL is a chroma- Writing, review, and/or revision of the manuscript: S.K. Zaidi, R.A. Grandy, tin-remodeling factor that is associated with leukemia and C. Lopez-Camacho, M. Montecino, A. van Wijnen, J.B. Lian, J. Stein, G.S. Stein regulates transcription by recruiting chromatin modifying machinery to target genes. This mitotic retention favors Grant Support These studies were in part supported by the grants from the NIH (P01 rapid reactivation of target genes required for the onset and CA082834 and P01 AR48818 to G.S. Stein; R01 AR039588 to G.S. Stein and J.B. progression of MLL postmitotically (45). It will be infor- Lian; R03 CA167726 to S.K. Zaidi; and R37 DE 012528 to J.B. Lian) and FONDAP mative to establish whether mitotic bookmarking of cancer- (15090007 to M. Montecino). fi related genes is a shared trait of all sequence-speci c Received October 1, 2013; revised November 1, 2013; accepted November 4, oncogenic proteins. 2013; published OnlineFirst January 9, 2014.

References 1. Wang F, Higgins JMG. Histone modifications and mitosis: coun- 7. Prescott DM, Bender MA. Synthesis of RNA and protein during mitosis termarks, landmarks, and bookmarks. Trends Cell Biol 2013;23: in mammalian tissue culture cells. Exp Cell Res 1962;26:260–8. 175–84. 8. Bostock CJ, Christie S, Hatch FT. Accessibility of DNA in condensed 2. Margueron R, Reinberg D. Chromatin structure and the inheritance of chromatin to nuclease digestion. Nature 1976;262:516–9. epigenetic information. Nat Rev Genet 2010;11:285–96. 9. Xing H. Mechanism of hsp70i gene bookmarking. Science 2005;307: 3. Probst AV, Dunleavy E, Almouzni G. Epigenetic inheritance during the 421–3. cell cycle. Nat Rev Mol Cell Biol 2009;10:192–206. 10. Martínez-Balbas MA, Dey A, Rabindran SK, Ozato K, Wu C. Displace- 4. Sarkies P, Sale JE. Cellular epigenetic stability and cancer. Trends ment of sequence-specific transcription factors from mitotic chroma- Genet 2012;28:1–10. tin. Cell 1995;83:29–38. 5. Maeshima K, Hihara S, Takata H. New Insight into the mitotic chro- 11. Zaidi SK, Young DW, Pockwinse SM, Javed A, Lian JB, Stein JL, et al. mosome structure: irregular folding of nucleosome fibers without 30- Mitotic partitioning and selective reorganization of tissue-specific nm chromatin structure. Cold Spring Harb Symp Quant Biol 2011; transcription factors in progeny cells. Proc Natl Acad Sci U S A 2003; 75:439–44. 100:14852–7. 6. Taylor JH. Nucleic acid synthesis in relation to the cell division cycle. 12. Otto F, Lubbert€ M, Stock M. Upstream and downstream targets of Ann N Y Acad Sci 1960;90:409–21. RUNX proteins. J Cell Biochem 2003;89:9–18.

www.aacrjournals.org Cancer Res; 74(2) January 15, 2014 OF5

Zaidi et al.

13. Kadauke S, Udugama MI, Pawlicki JM, Achtman JC, Jain DP, Cheng Y, 28. Pande S, Ali SA, Dowdy CR, Zaidi SK, Ito K, Ito Y, et al. Subnuclear et al. Tissue-specific mitotic bookmarking by hematopoietic transcrip- targeting of the Runx3 tumor suppressor and its epigenetic association tion factor GATA1. Cell 2012;150:725–37. with mitotic chromosomes. J Cell Physiol 2009;218:473–9. 14. Caravaca JM, Donahue G, Becker JS, He X, Vinson C, Zaret KS. 29. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional Bookmarking by specific and nonspecific binding of FoxA1 pioneer regulation of adipogenesis. Genes Dev 2000;14:1293–307. factor to mitotic chromosomes. Genes Dev 2013;27:251–60. 30. Zhao R, Nakamura T, Fu Y, Lazar Z, Spector DL. Gene bookmarking 15. DeyA,EllenbergJ,FarinaA,Coleman AE, Maruyama T, Sciortino S, accelerates the kinetics of post-mitotic transcriptional re-activation. et al. A bromodomain protein, MCAP, associates with mitotic Nat Publ Group 2011;13:1295–304. chromosomes and affects G(2)-to-M transition. Mol Cell Biol 2000; 31. Prasanth KV, Sacco-Bubulya PA, Prasanth SG, Spector DL. Sequen- 20:6537–49. tial entry of components of the gene expression machinery into 16. Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double daughter nuclei. Mol Biol Cell 2003;14:1043–57. bromodomain protein Brd4 binds to acetylated chromatin 32. John S, Workman JL. Bookmarking genes for activation in condensed during interphase and mitosis. Proc Natl Acad Sci U S A 2003;100: mitotic chromosomes. Bioessays 1998;20:275–9. 8758–63. 33. Ng RK, Gurdon JB. Epigenetic memory of an active gene state 17. Zaidi SK, Young DW, Javed A, Pratap J, Montecino MA, van Wijnen AJ, depends on histone H3.3 incorporation into chromatin in the absence et al. Nuclear microenvironments in biological control and cancer. Nat of transcription. Nat Cell Biol 2007;10:102–9. Rev Cancer 2007;7:454–63. 34. Kelly TK, Miranda TB, Liang G, Berman BP, Lin JC, Tanay A, et al. H2A. 18. Young DW, Hassan MQ, Pratap J, Galindo M, Zaidi SK, Lee S-H, et al. Z Maintenance during mitosis reveals nucleosome shifting on mitot- Mitotic occupancy and lineage-specific transcriptional control of rRNA ically silenced genes. Mol Cell 2010;39:901–11. genes by Runx2. Nature 2007;445:442–6. 35. Terrenoire E, McRonald F, Halsall JA, Page P, Illingworth RS, Taylor 19. Young DW, Hassan MQ, Yang X, Galindo M, Javed A, Zaidi SK, et al. AM, et al. Immunostaining of modified histones defines high-level Mitotic retention of gene expression patterns by the cell fate-deter- features of the human metaphase epigenome. Genome Biol 2010; mining transcription factor Runx2. Proc Natl Acad Sci U S A 2007; 11:R110. 104:3189–94. 36. Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, et al. Genome- 20. AliSA,DobsonJR,LianJB,SteinJL,vanWijnenAJ,ZaidiSK,etal. wide mapping of HATs and HDACs reveals distinct functions in active A Runx2-HDAC1 co-repressor complex regulates rRNA gene and inactive genes. Cell 2009;138:1019–31. expression by modulating UBF acetylation. J Cell Sci 2012;125: 37. Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, et al. Transcription 2732–9. factor binding in human cells occurs in dense clusters formed around 21. Dey A, Nishiyama A, Karpova T, McNally J, Ozato K. Brd4 marks select cohesin anchor sites. Cell 2013;154:801–13. genes on mitotic chromatin and directs postmitotic transcription. Mol 38. Rappsilber J, Earnshaw WC. Building mitotic chromosomes. Curr Opin Biol Cell 2009;20:4899–909. Cell Biol 2011;23:114–21. 22. Migliaccio AR, Rana RA, Vannucchi AM, Manzoli FA. Role of GATA-1 in 39. Kadauke S, Blobel GA. Mitotic bookmarking by transcription factors. normal and neoplastic hemopoiesis. Ann N Y Acad Sci 2005;1044: Epigenetics Chromatin 2013;6:1–1. 142–58. 40. Di Talia S, Wang H, Skotheim JM, Rosebrock AP, Futcher B, Cross FR. 23. Friedman JR, Kaestner KH. The Foxa family of transcription Daughter-specific transcription factors regulate cell size control in factors in development and metabolism. Cell Mol Life Sci 2006;63: budding yeast. PLoS Biol 2009;7:e1000221. 2317–28. 41. Hirata J, Nakagoshi H, Nabeshima Y, Matsuzaki F. Asymmetric seg- 24. Ali SA, Zaidi SK, Dacwag CS, Salma N, Young DW, Shakoori AR, et al. regation of the homeodomain protein Prospero during Drosophila Phenotypic transcription factors epigenetically mediate cell growth development. Nature 1995;377:627–30. control. Proc Natl Acad Sci U S A 2008;105:6632–7. 42. Aakre CD, Laub MT. Asymmetric cell division: a persistent issue? Dev 25. Tang QQ, Lane MD. Activation and centromeric localization of CCAAT/ Cell 2012;22:235–6. enhancer-binding proteins during the mitotic clonal expansion of 43. Knoblich JA. Asymmetric cell division: recent developments and their adipocyte differentiation. Genes Dev 1999;13:2231–41. implications for tumour biology. Nat Rev Mol Cell Biol 2010;11:849–60. 26. Berkes CA, Tapscott SJ. MyoD and the transcriptional control of 44. Roegiers F, Jan YN. Asymmetric cell division. Curr Opin Cell Biol 2004; myogenesis. Semin Cell Dev Biol 2005;16:585–95. 16:195–205. 27. Bakshi R, Zaidi SK, Pande S, Hassan MQ, Young DW, Montecino M, 45. Blobel GA, Kadauke S, Wang E, Lau AW, Zuber J, Chou MM, et al. A et al. The leukemogenic t(8;21) fusion protein AML1-ETO controls reconfigured pattern of MLL occupancy within mitotic chromatin rRNA genes and associates with nucleolar-organizing regions at promotes rapid transcriptional reactivation following mitotic exit. Mol mitotic chromosomes. J Cell Sci 2008;121:3981–90. Cell 2009;36:970–83.

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Bookmarking Target Genes in Mitosis: A Shared Epigenetic Trait of Phenotypic Transcription Factors and Oncogenes?

Sayyed K. Zaidi, Rodrigo A. Grandy, Cesar Lopez-Camacho, et al.

Cancer Res Published OnlineFirst January 9, 2014.

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