Transcriptional control of embryonic and induced pluripotent stem cells.

Embryonic stem cells (ESCs) have the potential to generate virtually any cell type or tissue type in the body. This remarkable plasticity has yielded great interest in using these cells to understand early development and in treating human disease. In an effort to understand the basis of ESC pluripotency, genetic and genomic studies have revealed transcriptional regulatory circuitry that maintains the pluripotent cell state and poises the genome for downstream activation. Critical components of this circuitry include ESC transcription factors, chromatin regulators, histone modifications, signaling molecules and regulatory RNAs. This article will focus on our current understanding of these components and how they influence ESC and induced pluripotent stem cell states. Emerging themes include regulation of the pluripotent genome by a core set of transcription factors, transcriptional poising of developmental genes by chromatin regulatory complexes and the establishment of multiple layers of repression at key genomic loci.

[1]  Ha-won Jeong,et al.  Stem Cell Factor SALL4 Represses the Transcriptions of PTEN and SALL1 through an Epigenetic Repressor Complex , 2009, PloS one.

[2]  Xi Chen,et al.  Reciprocal Transcriptional Regulation of Pou5f1 and Sox2 via the Oct4/Sox2 Complex in Embryonic Stem Cells , 2005, Molecular and Cellular Biology.

[3]  Li Chai,et al.  Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells , 2008, Proceedings of the National Academy of Sciences.

[4]  V. Pirrotta,et al.  Drosophila Enhancer of Zeste/ESC Complexes Have a Histone H3 Methyltransferase Activity that Marks Chromosomal Polycomb Sites , 2002, Cell.

[5]  Richard A Young,et al.  Wnt signaling promotes reprogramming of somatic cells to pluripotency. , 2008, Cell stem cell.

[6]  C. Allis,et al.  Operating on chromatin, a colorful language where context matters. , 2011, Journal of molecular biology.

[7]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[8]  J. Nichols,et al.  BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3 , 2003, Cell.

[9]  G. Stein,et al.  Pluripotency: Toward a gold standard for human ES and iPS cells , 2009, Journal of cellular physiology.

[10]  Radu Dobrin,et al.  Dissecting self-renewal in stem cells with RNA interference , 2006, Nature.

[11]  Atul J Butte,et al.  MicroRNA profiling of human-induced pluripotent stem cells. , 2009, Stem cells and development.

[12]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[13]  Stuart L. Schreiber,et al.  Active genes are tri-methylated at K4 of histone H3 , 2002, Nature.

[14]  Howard Y. Chang,et al.  Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes , 2010, Science.

[15]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

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

[17]  Michael B. Stadler,et al.  Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. , 2008, Molecular cell.

[18]  Tomohiro Kono,et al.  Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells , 2010, Nature.

[19]  Stuart L. Schreiber,et al.  Methylation of histone H3 Lys 4 in coding regions of active genes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  H. Ng,et al.  T‐Cell Factor 3 Regulates Embryonic Stem Cell Pluripotency and Self‐Renewal by the Transcriptional Control of Multiple Lineage Pathways , 2008, Stem cells.

[21]  Tony Kouzarides,et al.  Histone H3 lysine 4 methylation patterns in higher eukaryotic genes , 2004, Nature Cell Biology.

[22]  E. Seto,et al.  The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men , 2008, Nature Reviews Molecular Cell Biology.

[23]  M. Pellegrini,et al.  Molecular analyses of human induced pluripotent stem cells and embryonic stem cells. , 2010, Cell stem cell.

[24]  Austin G Smith,et al.  The ground state of pluripotency. , 2010, Biochemical Society transactions.

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

[26]  A. Bird,et al.  Genomic DNA methylation: the mark and its mediators. , 2006, Trends in biochemical sciences.

[27]  R. Tjian,et al.  ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a , 2008, Proceedings of the National Academy of Sciences.

[28]  A. Shilatifard,et al.  The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes. , 2010, Molecular cell.

[29]  Herbert Schulz,et al.  A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. , 2009, Cell stem cell.

[30]  D. Charnock-Jones,et al.  The Role of Leukaemia Inhibitory Factor and Interleukin-6 in Human Reproduction , 2022 .

[31]  Juri Rappsilber,et al.  JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells , 2010, Nature.

[32]  M. Surani,et al.  The Polycomb-Group GeneEzh2 Is Required for Early Mouse Development , 2001, Molecular and Cellular Biology.

[33]  R. Young,et al.  A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells , 2007, Cell.

[34]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[35]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[36]  M. Surani,et al.  ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage , 2009, Epigenetics & Chromatin.

[37]  En Li,et al.  Suv 39 h-Mediated Histone H 3 Lysine 9 Methylation Directs DNA Methylation to Major Satellite Repeats at Pericentric Heterochromatin , 2003 .

[38]  Martin J Aryee,et al.  Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts , 2009, Nature Genetics.

[39]  G. Melen,et al.  Embryonic Stem Cell-Specific miR302-367 Cluster: Human Gene Structure and Functional Characterization of Its Core Promoter , 2008, Molecular and Cellular Biology.

[40]  Yi Zhang,et al.  SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. , 2004, Molecular cell.

[41]  A. Pombo,et al.  Ring1B and Suv39h1 delineate distinct chromatin states at bivalent genes during early mouse lineage commitment , 2010, Development.

[42]  M. Zavolan,et al.  MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells , 2008, Nature Structural &Molecular Biology.

[43]  M. Jaritz,et al.  Polycomb complexes act redundantly to repress genomic repeats and genes. , 2010, Genes & development.

[44]  K. Okamoto,et al.  A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells , 1990, Cell.

[45]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[46]  O. Dovey,et al.  Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation , 2010, Proceedings of the National Academy of Sciences.

[47]  H. Aburatani,et al.  Sall4 Is Essential for Stabilization, But Not for Pluripotency, of Embryonic Stem Cells by Repressing Aberrant Trophectoderm Gene Expression , 2009, Stem cells.

[48]  G. Kay,et al.  Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. , 2004, Molecular cell.

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

[50]  Aaron M. Newman,et al.  Lab-specific gene expression signatures in pluripotent stem cells. , 2010, Cell stem cell.

[51]  Y. Bergman,et al.  A Unique Developmental Pattern of Oct-3/4DNA Methylation Is Controlled by a cis-demodification Element* , 2002, The Journal of Biological Chemistry.

[52]  Chad A. Cowan,et al.  A high-efficiency system for the generation and study of human induced pluripotent stem cells. , 2008, Cell stem cell.

[53]  M. Pellegrini,et al.  Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency , 2010, Nature.

[54]  Mike J. Mason,et al.  Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. , 2009, Cell stem cell.

[55]  John T. Lis,et al.  Defining mechanisms that regulate RNA polymerase II transcription in vivo , 2009, Nature.

[56]  C. Glass,et al.  Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. , 2006, Genes & development.

[57]  Martin J. Aryee,et al.  Epigenetic memory in induced pluripotent stem cells , 2010, Nature.

[58]  Richard A Young,et al.  Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. , 2010, Cell stem cell.

[59]  S. Orkin,et al.  Jumonji Modulates Polycomb Activity and Self-Renewal versus Differentiation of Stem Cells , 2009, Cell.

[60]  Martin Vingron,et al.  Transcriptional Autoregulatory Loops Are Highly Conserved in Vertebrate Evolution , 2008, PloS one.

[61]  L. Kenner,et al.  Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans , 2010, The EMBO journal.

[62]  H. Kato,et al.  G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. , 2002, Genes & development.

[63]  Michael J. Ziller,et al.  Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines , 2011, Cell.

[64]  Krishanu Saha,et al.  Pluripotency and Cellular Reprogramming: Facts, Hypotheses, Unresolved Issues , 2010, Cell.

[65]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[66]  Yvonne Tay,et al.  MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation , 2008, Nature.

[67]  Leighton J. Core,et al.  Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters , 2008, Science.

[68]  Gang Li,et al.  Jarid2 and PRC2, partners in regulating gene expression. , 2010, Genes & development.

[69]  Ernest Fraenkel,et al.  Core transcriptional regulatory circuitry in human hepatocytes , 2006, Molecular systems biology.

[70]  Ryan A. Flynn,et al.  A unique chromatin signature uncovers early developmental enhancers in humans , 2011, Nature.

[71]  B. Blencowe,et al.  Regulation of Alternative Splicing by Histone Modifications , 2010, Science.

[72]  R. Jaenisch,et al.  In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state , 2007, Nature.

[73]  Shaorong Gao,et al.  Cell Stem Cell Brief Report Ips Cells Can Support Full-term Development of Tetraploid Blastocyst-complemented Embryos Cell Stem Cell Brief Report , 2022 .

[74]  M. Groudine,et al.  Functional and Mechanistic Diversity of Distal Transcription Enhancers , 2011, Cell.

[75]  B. Panning,et al.  An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity , 2008, Cell.

[76]  Jun Qin,et al.  Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells , 2008, Nature Cell Biology.

[77]  Alexei A. Sharov,et al.  Dissecting Oct3/4-Regulated Gene Networks in Embryonic Stem Cells by Expression Profiling , 2006, PloS one.

[78]  R. Young,et al.  Repressive Transcription , 2010, Science.

[79]  Jennifer A. Erwin,et al.  Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations , 2010, Cell.

[80]  Shridar Ganesan,et al.  Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. , 2005, Genes & development.

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

[82]  Christoforos Nikolaou,et al.  Nucleosome positioning as a determinant of exon recognition , 2009, Nature Structural &Molecular Biology.

[83]  Keji Zhao,et al.  An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network , 2009, Proceedings of the National Academy of Sciences.

[84]  Matteo Pellegrini,et al.  Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. , 2008, Cell stem cell.

[85]  M. Johnston,et al.  The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. , 2003, Molecular cell.

[86]  S. Raguz,et al.  Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. , 2010, Molecular cell.

[87]  Peter W. J. Rigby,et al.  A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo , 1990, Nature.

[88]  G. Crabtree,et al.  Chromatin regulatory mechanisms in pluripotency. , 2010, Annual review of cell and developmental biology.

[89]  Petr Svoboda,et al.  Maternal BRG1 regulates zygotic genome activation in the mouse. , 2006, Genes & development.

[90]  Krishanu Saha,et al.  Technical challenges in using human induced pluripotent stem cells to model disease. , 2009, Cell stem cell.

[91]  Christopher B. Burge,et al.  c-Myc Regulates Transcriptional Pause Release , 2010, Cell.

[92]  B. Cairns,et al.  The biology of chromatin remodeling complexes. , 2009, Annual review of biochemistry.

[93]  M. Cosma,et al.  Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. , 2008, Cell stem cell.

[94]  Hideyuki Okano,et al.  Variation in the safety of induced pluripotent stem cell lines , 2009, Nature Biotechnology.

[95]  Alexei A. Sharov,et al.  Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data , 2008, BMC Genomics.

[96]  S. Tillib,et al.  The bithorax complex is regulated by trithorax earlier during Drosophila embryogenesis than is the Antennapedia complex, correlating with a bithorax-like expression pattern of distinct early trithorax transcripts. , 1994, Development.

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

[98]  Nathaniel D. Heintzman,et al.  Histone modifications at human enhancers reflect global cell-type-specific gene expression , 2009, Nature.

[99]  J. Rinn,et al.  Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells , 2010, Nature Genetics.

[100]  Kristopher L. Nazor,et al.  Adult mice generated from induced pluripotent stem cells , 2009, Nature.

[101]  R. Jaenisch,et al.  A drug-inducible system for direct reprogramming of human somatic cells to pluripotency. , 2008, Cell stem cell.

[102]  W. Reik,et al.  Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal , 2009, Nature Reviews Molecular Cell Biology.

[103]  Oliver H. Tam,et al.  Characterization of Dicer-deficient murine embryonic stem cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[104]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[105]  G. Ast,et al.  Chromatin organization marks exon-intron structure , 2009, Nature Structural &Molecular Biology.

[106]  Kim Nasmyth,et al.  Cohesin: its roles and mechanisms. , 2009, Annual review of genetics.

[107]  H. Schöler,et al.  Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. , 1994, Developmental biology.

[108]  A. Smith,et al.  Embryo-derived stem cells: of mice and men. , 2001, Annual review of cell and developmental biology.

[109]  Sohail Malik,et al.  The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation , 2010, Nature Reviews Genetics.

[110]  Arend Sidow,et al.  Jarid2/Jumonji Coordinates Control of PRC2 Enzymatic Activity and Target Gene Occupancy in Pluripotent Cells , 2009, Cell.

[111]  M. Mallo,et al.  Hox genes and regional patterning of the vertebrate body plan. , 2010, Developmental biology.

[112]  R. Young,et al.  Histone H3K27ac separates active from poised enhancers and predicts developmental state , 2010, Proceedings of the National Academy of Sciences.

[113]  D. Spector,et al.  Long noncoding RNAs: functional surprises from the RNA world. , 2009, Genes & development.

[114]  Ping Zhu,et al.  Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. , 2008, Molecular cell.

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

[116]  T. Quertermous,et al.  Persistent Donor Cell Gene Expression among Human Induced Pluripotent Stem Cells Contributes to Differences with Human Embryonic Stem Cells , 2010, PloS one.

[117]  R. Lovell-Badge,et al.  Multipotent cell lineages in early mouse development depend on SOX2 function. , 2003, Genes & development.

[118]  P. Harte,et al.  Molecular characterization of the trithorax gene, a positive regulator of homeotic gene expression in Drosophila , 1991, Mechanisms of Development.

[119]  Juan M. Vaquerizas,et al.  A census of human transcription factors: function, expression and evolution , 2009, Nature Reviews Genetics.

[120]  Wei Li,et al.  Activation of the Imprinted Dlk1-Dio3 Region Correlates with Pluripotency Levels of Mouse Stem Cells , 2010, The Journal of Biological Chemistry.

[121]  G. Pan,et al.  MicroRNA-145 Regulates OCT4, SOX2, and KLF4 and Represses Pluripotency in Human Embryonic Stem Cells , 2009, Cell.

[122]  Li Chai,et al.  Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1 , 2006, Nature Cell Biology.

[123]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[124]  Jan Komorowski,et al.  Nucleosomes are well positioned in exons and carry characteristic histone modifications. , 2009, Genome research.

[125]  Ying Jin,et al.  Critical Roles of Coactivator p300 in Mouse Embryonic Stem Cell Differentiation and Nanog Expression* , 2009, Journal of Biological Chemistry.

[126]  K. Hochedlinger,et al.  Epigenetic reprogramming and induced pluripotency , 2009, Development.

[127]  Yuriy L Orlov,et al.  Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. , 2009, Genes & development.

[128]  Fred H. Gage,et al.  Transcriptional Signature and Memory Retention of Human-Induced Pluripotent Stem Cells , 2009, PloS one.

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

[130]  Yuri B Schwartz,et al.  Polycomb complexes and epigenetic states. , 2008, Current opinion in cell biology.

[131]  Helen M. Rowe,et al.  KAP1 controls endogenous retroviruses in embryonic stem cells , 2010, Nature.

[132]  Debbie L C van den Berg,et al.  An Oct4-Centered Protein Interaction Network in Embryonic Stem Cells , 2010, Cell stem cell.

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

[134]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[135]  V. Orlando,et al.  General transcription factors bind promoters repressed by Polycomb group proteins , 2001, Nature.

[136]  S. Berger.  The complex language of chromatin regulation during transcription , 2007, Nature.

[137]  H. Blau,et al.  Nuclear reprogramming to a pluripotent state by three approaches , 2010, Nature.

[138]  Eric S. Lander,et al.  Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse , 2005, Cell.

[139]  J. Rinn,et al.  Non-coding RNAs as regulators of embryogenesis , 2011, Nature Reviews Genetics.

[140]  N. D. Clarke,et al.  A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity , 2010, Nature.

[141]  X. Chen,et al.  Sall4 Interacts with Nanog and Co-occupies Nanog Genomic Sites in Embryonic Stem Cells* , 2006, Journal of Biological Chemistry.

[142]  Austin G Smith,et al.  Self-renewal of teratocarcinoma and embryonic stem cells , 2004, Oncogene.

[143]  Danny Reinberg,et al.  Molecular Signals of Epigenetic States , 2010, Science.

[144]  K. Hochedlinger,et al.  Induced pluripotency: history, mechanisms, and applications. , 2010, Genes & development.

[145]  I. Krantz,et al.  Cornelia de Lange syndrome, cohesin, and beyond , 2009, Clinical genetics.

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

[147]  J. V. Falvo,et al.  Structure and Function of the Interferon-β Enhanceosome , 1998 .

[148]  Kevin Struhl,et al.  Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. , 2003, Molecular cell.

[149]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[150]  Robert S Illingworth,et al.  CpG islands – ‘A rough guide’ , 2009, FEBS letters.

[151]  J. Komorowski,et al.  Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. , 2008, Molecular cell.

[152]  Ruchir Shah,et al.  RNA polymerase is poised for activation across the genome , 2007, Nature Genetics.

[153]  R. Tjian,et al.  Transcription regulation and animal diversity , 2003, Nature.

[154]  A. Shilatifard,et al.  An operational definition of epigenetics. , 2009, Genes & development.

[155]  Ge Guo,et al.  Nanog Is the Gateway to the Pluripotent Ground State , 2009, Cell.

[156]  Jim Stalker,et al.  A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci , 2008, PLoS biology.

[157]  Rudolf Jaenisch,et al.  Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors , 2009, Cell.

[158]  K. Hochedlinger,et al.  Tgfβ Signal Inhibition Cooperates in the Induction of iPSCs and Replaces Sox2 and cMyc , 2009, Current Biology.

[159]  Haruhiko Koseki,et al.  Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. , 2004, Developmental cell.

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

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

[162]  A. Shilatifard,et al.  Histone H3 lysine 4 (H3K4) methylation in development and differentiation. , 2010, Developmental biology.

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

[164]  M. Babu,et al.  An Expanded Oct4 Interaction Network: Implications for Stem Cell Biology, Development, and Disease , 2010, Cell stem cell.

[165]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[166]  S. Lehnert,et al.  Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. , 1987, Development.

[167]  Amos Tanay,et al.  Functional Anatomy of Polycomb and Trithorax Chromatin Landscapes in Drosophila Embryos , 2009, PLoS biology.

[168]  E. Lander,et al.  The Mammalian Epigenome , 2007, Cell.

[169]  Jennifer Nichols,et al.  Promotion of Reprogramming to Ground State Pluripotency by Signal Inhibition , 2008, PLoS biology.

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

[171]  Yuriy L Orlov,et al.  The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. , 2010, Cell stem cell.

[172]  D. Reinberg,et al.  Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. , 2002, Genes & development.

[173]  G. Pan,et al.  Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. , 2007, Cell stem cell.

[174]  Wenjun Guo,et al.  Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds , 2008, Nature Biotechnology.

[175]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[176]  Atif Shahab,et al.  Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. , 2007, Cell stem cell.

[177]  Cassandra R. Farthing,et al.  Global Mapping of DNA Methylation in Mouse Promoters Reveals Epigenetic Reprogramming of Pluripotency Genes , 2008, PLoS genetics.

[178]  J. Chu,et al.  The transcriptional network controlling pluripotency in ES cells. , 2008, Cold Spring Harbor symposia on quantitative biology.

[179]  H. Kimura,et al.  Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET , 2010, Nature.

[180]  Rudolf Jaenisch,et al.  DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal , 2007, Nature Genetics.

[181]  J. Nichols,et al.  Nanog safeguards pluripotency and mediates germline development , 2007, Nature.

[182]  Robert S. Illingworth,et al.  CpG islands influence chromatin structure via the CpG-binding protein Cfp1 , 2010, Nature.

[183]  Alexei A. Sharov,et al.  Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells , 2007, Nature Cell Biology.

[184]  Stephan Sauer,et al.  Chromatin signatures of pluripotent cell lines , 2006, Nature Cell Biology.

[185]  P. Ingham.  trithorax and the regulation of homeotic gene expression in Drosophila: a historical perspective. , 1998, The International journal of developmental biology.

[186]  M S German,et al.  Autoregulation and Maturity Onset Diabetes of the Young Transcription Factors Control the Human PAX4 Promoter* , 2000, The Journal of Biological Chemistry.

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

[188]  Howard Cedar,et al.  DNA methylation represses transcription in vivo , 1999, Nature Genetics.

[189]  Kevin Eggan,et al.  Progress toward the clinical application of patient-specific pluripotent stem cells. , 2010, The Journal of clinical investigation.

[190]  Helen M. Blau,et al.  Reprogramming towards pluripotency requires AID-dependent DNA demethylation , 2010, Nature.

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

[192]  Marius Wernig,et al.  A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types , 2008, Nature Biotechnology.

[193]  Hans R. Schöler,et al.  New type of POU domain in germ line-specific protein Oct-4 , 1990, Nature.

[194]  Satoshi Tanaka,et al.  PGC7/Stella protects against DNA demethylation in early embryogenesis , 2007, Nature Cell Biology.

[195]  Wenjun Guo,et al.  Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2 , 2008, Nature Biotechnology.

[196]  A. Wood,et al.  Condensin and cohesin complexity: the expanding repertoire of functions , 2010, Nature Reviews Genetics.

[197]  J. Nichols,et al.  Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells , 2007, Development.

[198]  P. Greengard,et al.  Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor , 2004, Nature Medicine.

[199]  C. Allis,et al.  DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA , 2007, Nature.

[200]  V. Vega,et al.  Transcriptional regulatory networks in embryonic stem cells. , 2008, Cold Spring Harbor symposia on quantitative biology.

[201]  S. Yamanaka,et al.  Intracellular signaling pathways regulating pluripotency of embryonic stem cells. , 2006, Current stem cell research & therapy.

[202]  Richard A Young,et al.  Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. , 2010, Molecular cell.

[203]  M. Yaniv,et al.  The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression , 2000, EMBO reports.

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

[205]  G. Hannon,et al.  A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases , 2008, Nature Structural &Molecular Biology.

[206]  Luca Mazzarella,et al.  Jarid2 is a PRC2 component in embryonic stem cells required for multi-lineage differentiation and recruitment of PRC1 and RNA Polymerase II to developmental regulators , 2010, Nature Cell Biology.

[207]  J. Ahringer,et al.  Differential chromatin marking of introns and expressed exons by H3K36me3 , 2008, Nature Genetics.

[208]  Eric S. Lander,et al.  Dissecting direct reprogramming through integrative genomic analysis , 2008, Nature.

[209]  T. Mikkelsen,et al.  Genome-scale DNA methylation maps of pluripotent and differentiated cells , 2008, Nature.

[210]  R. Walczak,et al.  Autoregulation of the Human Liver X Receptor α Promoter , 2001, Molecular and Cellular Biology.

[211]  Sheng Ding,et al.  Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. , 2008, Cell stem cell.

[212]  Keesook Lee,et al.  Srg3, a Mouse Homolog of Yeast SWI3, Is Essential for Early Embryogenesis and Involved in Brain Development , 2001, Molecular and Cellular Biology.

[213]  T. Graf,et al.  Heterogeneity of embryonic and adult stem cells. , 2008, Cell stem cell.

[214]  A. Sands,et al.  Disruption of Ini1 Leads to Peri-Implantation Lethality and Tumorigenesis in Mice , 2001, Molecular and Cellular Biology.

[215]  A. Shilatifard.  Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. , 2008, Current opinion in cell biology.

[216]  J. Voncken,et al.  Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[217]  G. Crabtree,et al.  Chromatin remodelling during development , 2010, Nature.

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

[219]  Richard A Young,et al.  Global and Hox-specific roles for the MLL1 methyltransferase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[220]  R. Stewart,et al.  Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells , 2011, Nature.

[221]  P. Robson,et al.  Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. , 2008, Cell stem cell.

[222]  K. Kinzler,et al.  The Antisense Transcriptomes of Human Cells , 2008, Science.

[223]  Qi Zhou,et al.  iPS cells produce viable mice through tetraploid complementation , 2009, Nature.

[224]  R. Young,et al.  Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming , 2008, Cell.

[225]  Richard A Young,et al.  Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. , 2008, Genes & development.

[226]  Marius Wernig,et al.  c-Myc is dispensable for direct reprogramming of mouse fibroblasts. , 2008, Cell stem cell.

[227]  Brigitte Wild,et al.  Histone Methyltransferase Activity of a Drosophila Polycomb Group Repressor Complex , 2002, Cell.

[228]  H. Schöler,et al.  A combined chemical and genetic approach for the generation of induced pluripotent stem cells. , 2008, Cell stem cell.

[229]  D. Reinberg,et al.  Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. , 2004, Genes & development.

[230]  Arkady B. Khodursky,et al.  Global analysis of mRNA decay and abundance in Escherichia coli at single-gene resolution using two-color fluorescent DNA microarrays , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[232]  Marcos J. Araúzo-Bravo,et al.  Chromatin-Remodeling Components of the BAF Complex Facilitate Reprogramming , 2010, Cell.

[233]  A. Visel,et al.  ChIP-seq accurately predicts tissue-specific activity of enhancers , 2009, Nature.

[234]  Nevan J. Krogan,et al.  COMPASS: A complex of proteins associated with a trithorax-related SET domain protein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[235]  Giacomo Cavalli,et al.  Recruitment of Polycomb group complexes and their role in the dynamic regulation of cell fate choice , 2009, Development.

[236]  Jeffrey L. Wrana,et al.  Baf60c is essential for function of BAF chromatin remodelling complexes in heart development , 2004, Nature.

[237]  Donald Metcalf,et al.  Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells , 1988, Nature.

[238]  S. Tapscott,et al.  The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription , 2005, Development.

[239]  Kwang-Soo Kim,et al.  Hemangioblastic Derivatives from Human Induced Pluripotent Stem Cells Exhibit Limited Expansion and Early Senescence , 2010, Stem cells.

[240]  M. Rauchman,et al.  A Conserved 12-Amino Acid Motif in Sall1 Recruits the Nucleosome Remodeling and Deacetylase Corepressor Complex* , 2006, Journal of Biological Chemistry.

[241]  Sheng Zhong,et al.  A core Klf circuitry regulates self-renewal of embryonic stem cells , 2008, Nature Cell Biology.

[242]  T. Magnuson,et al.  The mouse PcG gene eed is required for Hox gene repression and extraembryonic development , 2002, Mammalian Genome.

[243]  Stephen J. Tapscott,et al.  Positive autoregulation of the myogenic determination gene MyoD1 , 1989, Cell.

[244]  James A Thomson,et al.  Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency , 2010, Proceedings of the National Academy of Sciences.

[245]  Richard A Young,et al.  Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. , 2008, Genes & development.

[246]  F. Tang,et al.  Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. , 2008, Cell stem cell.

[247]  Haruhiko Koseki,et al.  Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells , 2007, Nature Cell Biology.

[248]  Qikai Xu,et al.  A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. , 2009, Genes & development.

[249]  V. Cunliffe.  Eloquent silence: developmental functions of Class I histone deacetylases , 2008, Current opinion in genetics & development.

[250]  Jeannie T. Lee,et al.  Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome , 2008, Science.

[251]  Kristian Helin,et al.  Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. , 2006, Genes & development.

[252]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[253]  J. Nichols,et al.  The NuRD component Mbd3 is required for pluripotency of embryonic stem cells , 2006, Nature Cell Biology.

[254]  A. Razin,et al.  Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line. , 1992, Genes & development.

[255]  T. Kerppola.  Polycomb group complexes--many combinations, many functions. , 2009, Trends in cell biology.

[256]  Robert A. Martienssen,et al.  Noncoding RNAs and Gene Silencing , 2007, Cell.

[257]  Tao Wang,et al.  Esrrb Activates Oct4 Transcription and Sustains Self-renewal and Pluripotency in Embryonic Stem Cells* , 2008, Journal of Biological Chemistry.

[258]  M. Vidal,et al.  Role of histone H2A ubiquitination in Polycomb silencing , 2004, Nature.

[259]  H. Schöler,et al.  Modulation of the Activity of Multiple Transcriptional Activation Domains by the DNA Binding Domains Mediates the Synergistic Action of Sox2 and Oct-3 on the Fibroblast Growth Factor-4Enhancer* , 2000, The Journal of Biological Chemistry.

[260]  Manolis Kellis,et al.  RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo , 2007, Nature Genetics.

[261]  M. van Lohuizen,et al.  Stem cell regulation by polycomb repressors: postponing commitment. , 2008, Current opinion in cell biology.

[262]  E. Lewis.  A gene complex controlling segmentation in Drosophila , 1978, Nature.

[263]  Gene W. Yeo,et al.  Divergent Transcription from Active Promoters , 2008, Science.

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

[265]  L. Boyer,et al.  Polycomb group proteins set the stage for early lineage commitment. , 2010, Cell stem cell.