The abbreviated pluripotent cell cycle

Human embryonic stem cells (hESCs) and induced pluripotent stem cells proliferate rapidly and divide symmetrically producing equivalent progeny cells. In contrast, lineage committed cells acquire an extended symmetrical cell cycle. Self‐renewal of tissue‐specific stem cells is sustained by asymmetric cell division where one progeny cell remains a progenitor while the partner progeny cell exits the cell cycle and differentiates. There are three principal contexts for considering the operation and regulation of the pluripotent cell cycle: temporal, regulatory, and structural. The primary temporal context that the pluripotent self‐renewal cell cycle of hESCs is a short G1 period without reducing periods of time allocated to S phase, G2, and mitosis. The rules that govern proliferation in hESCs remain to be comprehensively established. However, several lines of evidence suggest a key role for the naïve transcriptome of hESCs, which is competent to stringently regulate the embryonic stem cell (ESC) cell cycle. This supports the requirements of pluripotent cells to self‐propagate while suppressing expression of genes that confer lineage commitment and/or tissue specificity. However, for the first time, we consider unique dimensions to the architectural organization and assembly of regulatory machinery for gene expression in nuclear microenviornments that define parameters of pluripotency. From both fundamental biological and clinical perspectives, understanding control of the abbreviated ESC cycle can provide options to coordinate control of proliferation versus differentiation. Wound healing, tissue engineering, and cell‐based therapy to mitigate developmental aberrations illustrate applications that benefit from knowledge of the biology of the pluripotent cell cycle. J. Cell. Physiol. 228: 9–20, 2013. © 2012 Wiley Periodicals, Inc.

[1]  Stephen Dalton,et al.  Myc represses primitive endoderm differentiation in pluripotent stem cells. , 2010, Cell stem cell.

[2]  A. Pardee,et al.  A restriction point for control of normal animal cell proliferation. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Lawrence,et al.  Replication-dependent histone gene expression is related to Cajal body (CB) association but does not require sustained CB contact. , 2001, Molecular biology of the cell.

[4]  George Q. Daley,et al.  Reprogramming of human somatic cells to pluripotency with defined factors , 2008, Nature.

[5]  Donald C. Chang,et al.  Regulation of somatic cell reprogramming through inducible mir-302 expression , 2010, Nucleic acids research.

[6]  M. Lako,et al.  G 1 to S phase cell cycle transition in somatic and embryonic stem cells , 2008 .

[7]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[8]  G. Stein,et al.  Histone H4 proximal promoter mediates a complex transcriptional response during differentiation of 3T3L1 adipocytes , 1995, Journal of cellular physiology.

[9]  G. Stein,et al.  The subnuclear organization of histone gene regulatory proteins and 3′ end processing factors of normal somatic and embryonic stem cells is compromised in selected human cancer cell types , 2009, Journal of cellular physiology.

[10]  J B Lian,et al.  Transcription of histone H4, H3, and H1 cell cycle genes: promoter factor HiNF-D contains CDC2, cyclin A, and an RB-related protein. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Harper,et al.  The Cyclin E/Cdk2 Substrate and Cajal Body Component p220NPAT Activates Histone Transcription through a Novel LisH-Like Domain , 2003, Molecular and Cellular Biology.

[12]  M. Lako,et al.  G1 to S phase cell cycle transition in somatic and embryonic stem cells , 2008, Journal of anatomy.

[13]  Yang Xu,et al.  p53 and stem cells: new developments and new concerns. , 2010, Trends in cell biology.

[14]  G. Stein,et al.  Coordinate regulation of multiple histone mRNAs during the cell cycle in HeLa cells. , 1983, Nucleic acids research.

[15]  Rudolf Jaenisch,et al.  Molecular control of pluripotency. , 2006, Current opinion in genetics & development.

[16]  Mudit Gupta,et al.  Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. , 2011, Cell stem cell.

[17]  G. Stein,et al.  The nuclear matrix protein NMP-1 is the transcription factor YY1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Livingston,et al.  MYC recruits the TIP60 histone acetyltransferase complex to chromatin , 2003, EMBO reports.

[19]  T. Ichisaka,et al.  Generation of germline-competent induced pluripotent stem cells , 2007, Nature.

[20]  Andre J. van Wijnen,et al.  A network connecting Runx2, SATB2, and the miR-23a∼27a∼24-2 cluster regulates the osteoblast differentiation program , 2010, Proceedings of the National Academy of Sciences.

[21]  T. Kouzarides.  Chromatin Modifications and Their Function , 2007, Cell.

[22]  W. Tansey,et al.  Myc-mediated transcriptional repression by recruitment of histone deacetylase. , 2008, Cancer research.

[23]  G. Perini,et al.  A SP1/MIZ1/MYCN repression complex recruits HDAC1 at the TRKA and p75NTR promoters and affects neuroblastoma malignancy by inhibiting the cell response to NGF. , 2011, Cancer research.

[24]  E. Avvedimento,et al.  DNA oxidation drives Myc mediated transcription , 2010, Cell cycle.

[25]  X. Chen,et al.  The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells , 2006, Nature Genetics.

[26]  S. K. Zaidi,et al.  Mitotic bookmarking of genes: a novel dimension to epigenetic control , 2010, Nature Reviews Genetics.

[27]  David S. Lapointe,et al.  Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2 , 2007, Proceedings of the National Academy of Sciences.

[28]  G. Stein,et al.  Protein-DNA interactions in vivo upstream of a cell cycle-regulated human H4 histone gene. , 1987, Science.

[29]  B. Lüscher,et al.  Stimulation of c‐MYC transcriptional activity and acetylation by recruitment of the cofactor CBP , 2003, EMBO reports.

[30]  Carolyn J. Brown,et al.  Characterization of expression at the human XIST locus in somatic, embryonal carcinoma, and transgenic cell lines. , 2003, Genomics.

[31]  J A Thomson,et al.  Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. , 2000, Developmental biology.

[32]  Haiying Liu,et al.  Oct4 regulates the miR-302 cluster in P19 mouse embryonic carcinoma cells , 2011, Molecular Biology Reports.

[33]  G. Stein,et al.  Fine mapping of the chromatin structure of a cell cycle-regulated human H4 histone gene. , 1989, Journal of Biological Chemistry.

[34]  Hisashi Tanaka,et al.  Gene Regulation and Epigenetic Remodeling in Murine Embryonic Stem Cells by c-Myc , 2009, PloS one.

[35]  L. Szekely,et al.  Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. , 1994, Oncogene.

[36]  G. Stein,et al.  ATF1 and CREB trans-activate a cell cycle regulated histone H4 gene at a distal nuclear matrix associated promoter element. , 1997, Biochemistry.

[37]  N. Terada,et al.  A Heterogeneous Expression Pattern for Nanog in Embryonic Stem Cells , 2007, Stem cells.

[38]  G. Stein,et al.  Concerted control of multiple histone promoter factors during cell density inhibition of proliferation in osteosarcoma cells: reciprocal regulation of cell cycle-controlled and bone-related genes. , 1993, Cancer research.

[39]  G. Stein,et al.  Altered binding of human histone gene transcription factors during the shutdown of proliferation and onset of differentiation in HL-60 cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Lawrence,et al.  AURKB-mediated effects on chromatin regulate binding versus release of XIST RNA to the inactive chromosome , 2009, The Journal of cell biology.

[41]  A. Consiglio,et al.  Rem2 GTPase maintains survival of human embryonic stem cells as well as enhancing reprogramming by regulating p53 and cyclin D1. , 2010, Genes & development.

[42]  M. Osley.  The regulation of histone synthesis in the cell cycle. , 1991, Annual review of biochemistry.

[43]  P. J. Welch,et al.  Differentiation of Mouse Embryonic Stem Cells after RNA Interference‐Mediated Silencing of OCT4 and Nanog , 2006, Stem cells.

[44]  Daniel J. Hoeppner,et al.  Global transcription in pluripotent embryonic stem cells. , 2008, Cell stem cell.

[45]  Janet L Stein,et al.  Reprogramming the pluripotent cell cycle: Restoration of an abbreviated G1 phase in human induced pluripotent stem (iPS) cells , 2011, Journal of cellular physiology.

[46]  I. Khrebtukova,et al.  Transcriptome Profiling of Human and Murine ESCs Identifies Divergent Paths Required to Maintain the Stem Cell State , 2005, Stem cells.

[47]  G. Stein,et al.  The histone gene activator HINFP is a nonredundant cyclin E/CDK2 effector during early embryonic cell cycles , 2009, Proceedings of the National Academy of Sciences.

[48]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[49]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells , 2008, Cell.

[50]  Philip R. Gafken,et al.  Myc influences global chromatin structure , 2006, The EMBO journal.

[51]  Austin G Smith,et al.  Capturing Pluripotency , 2008, Cell.

[52]  Hans Clevers,et al.  The cancer stem cell: premises, promises and challenges , 2011, Nature Medicine.

[53]  S. K. Zaidi,et al.  Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2 , 2007, Nature.

[54]  G. Schatten,et al.  DNA Damage Responses in Human Induced Pluripotent Stem Cells and Embryonic Stem Cells , 2010, PloS one.

[55]  J. Rossant,et al.  Global Chromatin Architecture Reflects Pluripotency and Lineage Commitment in the Early Mouse Embryo , 2010, PloS one.

[56]  G. Stein,et al.  TRANSCRIPTIONAL CONTROL OF CELL CYCLE PROGRESSION: THE HISTONE GENE IS A PARADIGM FOR THE G1/S PHASE AND PROLIFERATION/DIFFERENTIATION TRANSITIONS , 1996, Cell biology international.

[57]  G. Stein,et al.  In vivo protein binding sites and nuclease hypersensitivity in the promoter region of a cell cycle regulated human H3 histone gene. , 1989, Nucleic acids research.

[58]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[59]  G. Stein,et al.  Coordination of protein‐DNA interactions in the promoters of human H4, H3, and H1 histone genes during the cell cycle, tumorigenesis, and development , 1991, Journal of cellular physiology.

[60]  J. Mendell.  miRiad Roles for the miR-17-92 Cluster in Development and Disease , 2008, Cell.

[61]  R. Blelloch,et al.  Cell cycle regulation by MicroRNAs in embryonic stem cells. , 2009, Cancer research.

[62]  J. Lawrence,et al.  Ectopic XIST transcripts in human somatic cells show variable expression and localization , 2003, Cytogenetic and Genome Research.

[63]  S. K. Zaidi,et al.  HiNF-P Directly Links the Cyclin E/CDK2/p220NPAT Pathway to Histone H4 Gene Regulation at the G1/S Phase Cell Cycle Transition , 2005, Molecular and Cellular Biology.

[64]  J. Qin,et al.  Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. , 2000, Genes & development.

[65]  A. Pardee.  G1 events and regulation of cell proliferation. , 1989, Science.

[66]  Stephen Dalton,et al.  The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming. , 2009, Cell stem cell.

[67]  R. Knight,et al.  FLASH is required for histone transcription and S-phase progression , 2006, Proceedings of the National Academy of Sciences.

[68]  Irina Neganova,et al.  An Important Role for CDK2 in G1 to S Checkpoint Activation and DNA Damage Response in Human Embryonic Stem Cells , 2011, Stem cells.

[69]  Stuart H. Orkin,et al.  A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription Programs , 2010, Cell.

[70]  C. Blattner,et al.  p53 in stem cells. , 2011, World journal of biological chemistry.

[71]  A. Krämer,et al.  Cell-cycle regulation in embryonic stem cells: centrosomal decisions on self-renewal. , 2010, Stem cells and development.

[72]  M. Stojkovic,et al.  A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A , 2009, The Journal of cell biology.

[73]  Kristina Kapinas,et al.  MicroRNA biogenesis and regulation of bone remodeling , 2011, Arthritis research & therapy.

[74]  Donald C. Chang,et al.  MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways. , 2010, Cancer research.

[75]  G. Stein,et al.  MicroRNA control of bone formation and homeostasis , 2012, Nature Reviews Endocrinology.

[76]  R. Quigg,et al.  miR-17-92 cluster accelerates adipocyte differentiation by negatively regulating tumor-suppressor Rb2/p130 , 2008, Proceedings of the National Academy of Sciences.

[77]  C. Murphy,et al.  The Drosophila melanogaster Cajal body , 2006, The Journal of cell biology.

[78]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[79]  G. Stein,et al.  Regulation of human histone gene expression: transcriptional and posttranscriptional control in the coupling of histone messenger RNA stability with DNA replication. , 1987, Biochemistry.

[80]  A. Matera,et al.  Coiled bodies contain U7 small nuclear RNA and associate with specific DNA sequences in interphase human cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[81]  J. Gall,et al.  Coilin can form a complex with the U7 small nuclear ribonucleoprotein. , 1998, Molecular biology of the cell.

[82]  G. Stein,et al.  Involvement of the 5'-leader sequence in coupling the stability of a human H3 histone mRNA with DNA replication. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[83]  G. Stein,et al.  Multiple mechanisms regulate the proliferation-specific histone gene transcription factor HiNF-D in normal human diploid fibroblasts. , 1992, Biochemistry.

[84]  G. Stein,et al.  Staged assembly of histone gene expression machinery at subnuclear foci in the abbreviated cell cycle of human embryonic stem cells , 2008, Proceedings of the National Academy of Sciences.

[85]  S. Dalton,et al.  Myc orchestrates a regulatory network required for the establishment and maintenance of pluripotency , 2011, Cell cycle.

[86]  S. Dalton,et al.  LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism , 2005, Development.

[87]  G S Stein,et al.  Overlapping and CpG methylation-sensitive protein-DNA interactions at the histone H4 transcriptional cell cycle domain: distinctions between two human H4 gene promoters , 1992, Molecular and cellular biology.

[88]  G. Stein,et al.  Cytokine induction of proliferation and expression of CDC2 and cyclin a in FDC‐P1 myeloid hematopoietic progenitor cells: Regulation of ubiquitous and cell cycle‐dependent histone gene transcription factors , 1995, Journal of cellular biochemistry.

[89]  T. Ichisaka,et al.  GENERATION OF GERMLINECOMPETENT INDUCED PLURIPOTENT STEM CELLS , 2007 .

[90]  R. Young,et al.  SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. , 2009, Genes & development.

[91]  J. Mcneil,et al.  The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[92]  B. Kennedy,et al.  NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. , 2000, Genes & development.

[93]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[94]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[95]  J. C. Belmonte,et al.  LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells , 2011, Nature Cell Biology.

[96]  B. Frenkel,et al.  Functional role for Sp1 in the transcriptional amplification of a cell cycle regulated histone H4 gene. , 1995, Biochemistry.

[97]  J. Lawrence,et al.  An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[98]  B. Dynlacht,et al.  Expression of NPAT, a novel substrate of cyclin E-CDK2, promotes S-phase entry. , 1998, Genes & development.

[99]  Duncan Walker,et al.  Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities , 2002, Oncogene.

[100]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[101]  M. Eilers,et al.  Mechanisms of transcriptional repression by Myc. , 2006, Current topics in microbiology and immunology.

[102]  G. Stein,et al.  Reversible changes in the nucleosomal organization of a human H4 histone gene during the cell cycle. , 1986, Biochemistry.

[103]  G. Stein,et al.  In vivo occupancy of histone gene proximal promoter elements reflects gene copy number‐dependent titratable transactivation factors and cross‐species compatibility of regulatory sequences , 1995, Journal of cellular biochemistry.

[104]  Patrick J. Paddison,et al.  Smarcc1/Baf155 Couples Self‐Renewal Gene Repression with Changes in Chromatin Structure in Mouse Embryonic Stem Cells , 2009, Stem cells.

[105]  Federico Calegari,et al.  Cdks and cyclins link G1 length and differentiation of embryonic, neural and hematopoietic stem cells , 2010, Cell cycle.

[106]  J. Lawrence,et al.  The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade. , 2003, Seminars in cell & developmental biology.

[107]  J. Zeitlinger,et al.  Polycomb complexes repress developmental regulators in murine embryonic stem cells , 2006, Nature.

[108]  G S Stein,et al.  CDP/cut is the DNA-binding subunit of histone gene transcription factor HiNF-D: a mechanism for gene regulation at the G1/S phase cell cycle transition point independent of transcription factor E2F. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[110]  D. Prescott.  THE SYNTHESES OF TOTAL MACRONUCLEAR PROTEIN, HISTONE, AND DNA DURING THE CELL CYCLE IN EUPLOTES EURYSTOMUS , 1966, The Journal of cell biology.

[111]  Michael T. McManus,et al.  Chd1 regulates open chromatin and pluripotency of embryonic stem cells , 2009, Nature.

[112]  G. Stein,et al.  Human embryonic stem cells are pre‐mitotically committed to self‐renewal and acquire a lengthened G1 phase upon lineage programming , 2010, Journal of cellular physiology.

[113]  G. Stein,et al.  Cell cycle‐dependent modifications in activities of pRb‐related tumor suppressors and proliferation‐specific CDP/cut homeodomain factors in murine hematopoietic progenitor cells , 1997, Journal of cellular biochemistry.

[114]  Juan Carlos Izpisua Belmonte,et al.  A High Proliferation Rate Is Required for Cell Reprogramming and Maintenance of Human Embryonic Stem Cell Identity , 2011, Current Biology.

[115]  G. Stein,et al.  Maintenance of Open Chromatin and Selective Genomic Occupancy at the Cell Cycle-Regulated Histone H4 Promoter during Differentiation of HL-60 Promyelocytic Leukemia Cells , 2003, Molecular and Cellular Biology.

[116]  P. Menéndez,et al.  The miR-302-367 cluster as a potential stemness regulator in ESCs , 2009, Cell cycle.

[117]  Jim Yang,et al.  Stat3 and c-Myc Genome-Wide Promoter Occupancy in Embryonic Stem Cells , 2008, PloS one.

[118]  Megan F. Cole,et al.  Mapping key features of transcriptional regulatory circuitry in embryonic stem cells. , 2008, Cold Spring Harbor symposia on quantitative biology.

[119]  M. Stojkovic,et al.  A role for NANOG in G 1 to S transition in human embryonic stem cells through direct binding of CDK 6 and CDC 25 A , 2009 .

[120]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[121]  J. Thomson,et al.  Differentiation of Human Embryonic Stem Cells Occurs through Symmetric Cell Division , 2005, Stem cells.

[122]  J. Harper,et al.  The Cyclin E/Cdk2 Substrate p220NPAT Is Required for S-Phase Entry, Histone Gene Expression, and Cajal Body Maintenance in Human Somatic Cells , 2003, Molecular and Cellular Biology.

[123]  S. Dalton,et al.  Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation. , 2005, Molecular biology of the cell.

[124]  J. Lawrence,et al.  XIST RNA and architecture of the inactive X chromosome: implications for the repeat genome. , 2010, Cold Spring Harbor symposia on quantitative biology.

[125]  Leping Li,et al.  Oct4/Sox2-Regulated miR-302 Targets Cyclin D1 in Human Embryonic Stem Cells , 2008, Molecular and Cellular Biology.

[126]  G. Stein,et al.  Delineation of a human histone H4 cell cycle element in vivo: the master switch for H4 gene transcription. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[127]  K. Boheler.  Stem cell pluripotency: A cellular trait that depends on transcription factors, chromatin state and a checkpoint deficient cell cycle , 2009, Journal of cellular physiology.

[128]  Mike J. Mason,et al.  Role of the Murine Reprogramming Factors in the Induction of Pluripotency , 2009, Cell.

[129]  G. Stein,et al.  Native genomic blotting: high-resolution mapping of DNase I-hypersensitive sites and protein-DNA interactions. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[130]  G. Stein,et al.  Regulation of cell cycle stage-specific transcription of histone genes from chromatin by non-histone chromosomal proteins , 1975, Nature.

[131]  Jungho Kim,et al.  Oct-4 controls cell-cycle progression of embryonic stem cells , 2009, The Biochemical journal.

[132]  Donald C. Chang,et al.  Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. , 2008, RNA.

[133]  Xin Zhang,et al.  Expression and functional analysis of G1 to S regulatory components reveals an important role for CDK2 in cell cycle regulation in human embryonic stem cells , 2009, Oncogene.

[134]  R. Puri,et al.  Gene expression in human embryonic stem cell lines: unique molecular signature. , 2004, Blood.

[135]  G. Stein,et al.  Cell cycle dependent phosphorylation and subnuclear organization of the histone gene regulator p220NPAT in human embryonic stem cells , 2007, Journal of cellular physiology.

[136]  E. Avvedimento,et al.  LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription , 2010, Oncogene.

[137]  G S Stein,et al.  Cell cycle controlled histone H1, H3, and H4 genes share unusual arrangements of recognition motifs for HiNF‐D supporting a coordinate promoter binding mechanism , 1994, Journal of cellular physiology.

[138]  A. Friedman.  Cell cycle and developmental control of hematopoiesis by Runx1 , 2009, Journal of cellular physiology.

[139]  M. Cole,et al.  The Essential Cofactor TRRAP Recruits the Histone Acetyltransferase hGCN5 to c-Myc , 2000, Molecular and Cellular Biology.

[140]  G. Stein,et al.  Establishment of histone gene regulation and cell cycle checkpoint control in human embryonic stem cells , 2007, Journal of cellular physiology.

[141]  G. Stein,et al.  A human histone H4 gene exhibits cell cycle-dependent changes in chromatin structure that correlate with its expression. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[142]  S. K. Zaidi,et al.  Identification of HiNF-P, a Key Activator of Cell Cycle-Controlled Histone H4 Genes at the Onset of S Phase , 2003, Molecular and Cellular Biology.

[143]  A. Giordano,et al.  The retinoblastoma gene is involved in multiple aspects of stem cell biology , 2006, Oncogene.

[144]  G. Stein,et al.  Coordinate Control and Selective Expression of the Full Complement of Replication-dependent Histone H4 Genes in Normal and Cancer Cells* , 2005, Journal of Biological Chemistry.

[145]  G. Stein,et al.  Human H4 histone gene transcription requires the proliferation-specific nuclear factor HiNF-D. Auxiliary roles for HiNF-C (Sp1-like) and HiNF-A (high mobility group-like). , 1989, The Journal of biological chemistry.

[146]  S. Murray,et al.  myc maintains embryonic stem cell pluripotency and self-renewal. , 2010, Differentiation; research in biological diversity.

[147]  Shujian Wu,et al.  Activation of a cell-cycle-regulated histone gene by the oncogenic transcription factor IRF-2 , 1995, Nature.

[148]  G. Stein,et al.  Purification and functional analysis of a novel leucine-zipper/nucleotide-fold protein, BZAP45, stimulating cell cycle regulated histone H4 gene transcription. , 2001, Biochemistry.

[149]  E. Meshorer,et al.  Chromatin plasticity and genome organization in pluripotent embryonic stem cells. , 2010, Current opinion in cell biology.

[150]  K. Helin,et al.  Regulation of stem cell differentiation by histone methyltransferases and demethylases. , 2008, Cold Spring Harbor symposia on quantitative biology.

[151]  Marzluff Wf.  Histone 3' ends: essential and regulatory functions. , 1992 .

[152]  G. Stein,et al.  Survival responses of human embryonic stem cells to DNA damage , 2009, Journal of cellular physiology.

[153]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[154]  Hannele Ruohola-Baker,et al.  Characterization of microRNAs involved in embryonic stem cell states. , 2010, Stem cells and development.

[155]  P. Knoepfler.  Why myc? An unexpected ingredient in the stem cell cocktail. , 2008, Cell stem cell.

[156]  Takashi Aoi,et al.  Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts , 2008, Nature Biotechnology.

[157]  G. Stein,et al.  Histone proteins in HeLa S3 cells are synthesized in a cell cycle stage specific manner. , 1982, Science.

[158]  G. Stein,et al.  Live cell imaging of the cancer‐related transcription factor RUNX2 during mitotic progression , 2011, Journal of cellular physiology.

[159]  G. Stein,et al.  Self‐renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase , 2006, Journal of cellular physiology.

[160]  S. Stice,et al.  Comparative transcriptional profiling of two human embryonic stem cell lines , 2004, Biotechnology and bioengineering.

[161]  Sean J Morrison,et al.  Mechanisms of stem cell self-renewal. , 2009, Annual review of cell and developmental biology.

[162]  S. K. Zaidi,et al.  Control of the human pluripotent cell cycle , 2010 .