Epigenetics of embryonic stem cells.

Understanding the molecular mechanisms involved in the control of cell differentiation during embryonic development is currently one of the main objectives of developmental biology. This knowledge will provide a basis for the development of new strategies in the field of regenerative medicine, one of the most promising weapons to fight many human diseases. Cell differentiation during embryonic development is controlled primarily by epigenetic factors, that is, mechanisms involved in the regulation of chromatin structure and gene expression. Here we describe the best known epigenetic modifications, and pathways, mainly focused on DNA methylation and histone modifications, and try to depict the state of art in our knowledge about epigenetic regulation of embryonic stem cell maintenance and differentiation.

[1]  H. Deng,et al.  Pluripotin Combined with Leukemia Inhibitory Factor Greatly Promotes the Derivation of Embryonic Stem Cell Lines from Refractory Strains , 2009, Stem cells.

[2]  Jian-Bing Fan,et al.  Human embryonic stem cells have a unique epigenetic signature. , 2006, Genome research.

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

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

[5]  T P Fleming,et al.  A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst. , 1987, Developmental biology.

[6]  P. Lansdorp,et al.  The Mammalian SIR2α Protein Has a Role in Embryogenesis and Gametogenesis , 2003, Molecular and Cellular Biology.

[7]  Paul Tempst,et al.  Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. , 2005, Molecular cell.

[8]  H. Willard,et al.  Chromatin of the Barr body: histone and non-histone proteins associated with or excluded from the inactive X chromosome. , 2003, Human molecular genetics.

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

[10]  Ronen Marmorstein,et al.  Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase. , 2003, Molecular cell.

[11]  L. Guarente,et al.  The Sir2 family of protein deacetylases. , 2004, Annual review of biochemistry.

[12]  C. Disteche,et al.  Dosage compensation in mammals: fine-tuning the expression of the X chromosome. , 2006, Genes & development.

[13]  R. Jaenisch,et al.  Loss of methylation activates Xist in somatic but not in embryonic cells. , 1995, Genes & development.

[14]  D. Aswad,et al.  Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. , 2001, Biochemistry.

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

[16]  M. Hottiger,et al.  Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going? , 2006, Microbiology and Molecular Biology Reviews.

[17]  A. Jeltsch,et al.  Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. , 2006, Trends in biochemical sciences.

[18]  David Sinclair,et al.  Sirtuins in mammals: insights into their biological function. , 2007, The Biochemical journal.

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

[20]  D. Reinberg,et al.  SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation , 2007, Nature.

[21]  Stuart Thomson,et al.  MSK2 and MSK1 mediate the mitogen‐ and stress‐induced phosphorylation of histone H3 and HMG‐14 , 2003, The EMBO journal.

[22]  K. Brennand,et al.  Reprogramming of Pancreatic β Cells into Induced Pluripotent Stem Cells , 2008, Current Biology.

[23]  Brian D. Strahl,et al.  A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression , 2003, Nature.

[24]  J. Hyllner,et al.  Human embryonic stem cell technologies and drug discovery , 2009, Journal of cellular physiology.

[25]  J. Utikal,et al.  Induced Pluripotent Stem Cells Generated Without Viral Integration , 2008, Science.

[26]  A. V. van Kuilenburg,et al.  Histone deacetylases (HDACs): characterization of the classical HDAC family. , 2003, The Biochemical journal.

[27]  Y. Shiba,et al.  Cardiac applications for human pluripotent stem cells. , 2009, Current pharmaceutical design.

[28]  S. Khorasanizadeh The Nucleosome From Genomic Organization to Genomic Regulation , 2004, Cell.

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

[30]  Y. Schwartz,et al.  Polycomb silencing blocks transcription initiation. , 2004, Molecular cell.

[31]  C. Niehrs Active DNA demethylation and DNA repair. , 2009, Differentiation; research in biological diversity.

[32]  M. Zernicka-Goetz,et al.  Histone arginine methylation regulates pluripotency in the early mouse embryo , 2007, Nature.

[33]  Saswati Banerjee,et al.  DNA methyltransferase inhibition induces mouse embryonic stem cell differentiation into endothelial cells. , 2010, Experimental cell research.

[34]  Michael B. Stadler,et al.  Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome , 2007, Nature Genetics.

[35]  S. Baylin,et al.  DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci , 2000, Nature Genetics.

[36]  I. Albert,et al.  Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome , 2007, Nature.

[37]  Kristian Helin,et al.  The emerging functions of histone demethylases. , 2008, Current opinion in genetics & development.

[38]  M. Surani,et al.  Germ Cell Specification in Mice , 2007, Science.

[39]  S. Jacobsen,et al.  DEMETER, a DNA Glycosylase Domain Protein, Is Required for Endosperm Gene Imprinting and Seed Viability in Arabidopsis , 2002, Cell.

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

[41]  P. Varga-Weisz,et al.  The regulation of ATP-dependent nucleosome remodelling factors. , 2007, Mutation research.

[42]  D. Reinberg,et al.  Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

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

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

[46]  P. Barlow,et al.  DNA synthesis in the preimplantation mouse embryo. , 1972, Journal of embryology and experimental morphology.

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

[48]  N. Benvenisty,et al.  The immunogenicity of human embryonic stem-derived cells. , 2004, Trends in biotechnology.

[49]  S. Oh,et al.  Generation, culture, and differentiation of human embryonic stem cells for therapeutic applications. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[50]  J. Davie,et al.  Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. , 2001, Genes & development.

[51]  W. Reik,et al.  Active demethylation of the paternal genome in the mouse zygote , 2000, Current Biology.

[52]  T. Bestor,et al.  Sex-specific exons control DNA methyltransferase in mammalian germ cells. , 1998, Development.

[53]  Xi Chen,et al.  Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. , 2007, Genes & development.

[54]  R. Guigó,et al.  The histone variant macroH2A is an epigenetic regulator of key developmental genes , 2009, Nature Structural &Molecular Biology.

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

[56]  H. Ng,et al.  Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. , 1997, Science.

[57]  Tom Misteli,et al.  Chromatin in pluripotent embryonic stem cells and differentiation , 2006, Nature Reviews Molecular Cell Biology.

[58]  Danny Reinberg,et al.  Human but Not Yeast CHD1 Binds Directly and Selectively to Histone H3 Methylated at Lysine 4 via Its Tandem Chromodomains* , 2005, Journal of Biological Chemistry.

[59]  M. Fraga,et al.  Cancer Genes Hypermethylated in Human Embryonic Stem Cells , 2008, PloS one.

[60]  K. Helin,et al.  Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. , 2008, Genes & development.

[61]  D. Sterner,et al.  Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. , 2006, Genes & development.

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

[63]  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.

[64]  R J Roberts,et al.  Recombinant Human DNA (Cytosine-5) Methyltransferase , 1999, The Journal of Biological Chemistry.

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

[66]  T. Takeuchi,et al.  Roles of jumonji and jumonji family genes in chromatin regulation and development , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[67]  Geoff Kelly,et al.  Specificity and mechanism of the histone methyltransferase Pr-Set7. , 2005, Genes & development.

[68]  M. Fraga,et al.  Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells , 2010, PloS one.

[69]  M. Pazin,et al.  Histone H4-K16 Acetylation Controls Chromatin Structure and Protein Interactions , 2006, Science.

[70]  Brian D. Strahl,et al.  Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1 , 2001, Current Biology.

[71]  P. Chambon,et al.  Electron microscopic and biochemical evidence that chromatin structure is a repeating unit , 1975, Cell.

[72]  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.

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

[74]  I. Talianidis,et al.  Histone modifications defining active genes persist after transcriptional and mitotic inactivation , 2005, The EMBO journal.

[75]  Helmut Gernsheim,et al.  W. H. Fox Talbot and the history of photography , 1977 .

[76]  S. Yagi,et al.  Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells , 2007, Genes to cells : devoted to molecular & cellular mechanisms.

[77]  C. Wijmenga,et al.  The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[78]  E. Barry,et al.  Epigenetic regulatory mechanisms during preimplantation development. , 2009, Birth defects research. Part C, Embryo today : reviews.

[79]  C. Allis,et al.  Histone and chromatin cross-talk. , 2003, Current opinion in cell biology.

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

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

[82]  B. Turner,et al.  Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations , 2006, Nature Genetics.

[83]  Jun Qin,et al.  N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. , 2003, Molecular cell.

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

[85]  S. Mujtaba,et al.  Structure and acetyl-lysine recognition of the bromodomain , 2007, Oncogene.

[86]  T. Bestor,et al.  DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. , 1997, Journal of molecular biology.

[87]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[88]  Christopher R. Vakoc,et al.  DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells , 2008, Molecular and Cellular Biology.

[89]  K. Scheidtmann,et al.  Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation , 2008, Nature Cell Biology.

[90]  G. Daley,et al.  Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming , 2009, Nature Biotechnology.

[91]  D. Reinberg,et al.  Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. , 2004, Molecular cell.

[92]  Howard Cedar,et al.  DNA methylation affects the formation of active chromatin , 1986, Cell.

[93]  C. Langford,et al.  CARM1 Is Required in Embryonic Stem Cells to Maintain Pluripotency and Resist Differentiation , 2009, Stem cells.

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

[95]  K. Mechtler,et al.  14‐3‐3 Proteins recognize a histone code at histone H3 and are required for transcriptional activation , 2008, The EMBO journal.

[96]  Cyrus Martin,et al.  The diverse functions of histone lysine methylation , 2005, Nature Reviews Molecular Cell Biology.

[97]  M. Zofall,et al.  High-Resolution Mapping of Changes in Histone-DNA Contacts of Nucleosomes Remodeled by ISW2 , 2002, Molecular and Cellular Biology.

[98]  K. Helin,et al.  Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. , 2008, Genes & development.

[99]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[100]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[101]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[102]  Yi Zhang,et al.  The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. , 2004, Current opinion in genetics & development.

[103]  Paul Tempst,et al.  Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. , 2004, Molecular cell.

[104]  M. Scott Vertebrate homeobox gene nomenclature , 1992, Cell.

[105]  N. Benvenisty,et al.  The tumorigenicity of human embryonic stem cells. , 2008, Advances in cancer research.

[106]  Benjamin A. Garcia,et al.  Regulation of HP1–chromatin binding by histone H3 methylation and phosphorylation , 2005, Nature.

[107]  R. Krumlauf,et al.  Hox codes and positional specification in vertebrate embryonic axes. , 1992, Annual review of cell biology.

[108]  Tanja Waldmann,et al.  HP1 Binds Specifically to Lys26-methylated Histone H1.4, whereas Simultaneous Ser27 Phosphorylation Blocks HP1 Binding* , 2005, Journal of Biological Chemistry.

[109]  S. Hochi,et al.  Active demethylation of paternal genome in mammalian zygotes. , 2009, The Journal of reproduction and development.

[110]  Ioannis Xenarios,et al.  Microarray Deacetylation Maps Determine Genome-Wide Functions for Yeast Histone Deacetylases , 2002, Cell.

[111]  S. Wolf The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans , 2009, Cellular and Molecular Life Sciences.

[112]  H. Zoghbi,et al.  Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. , 1999, American journal of human genetics.

[113]  M. Fraga,et al.  The Polycomb group protein EZH2 directly controls DNA methylation , 2006, Nature.

[114]  J. Gearhart New Potential for Human Embryonic Stem Cells , 1998, Science.

[115]  S. Henikoff,et al.  Epigenetics, histone H3 variants, and the inheritance of chromatin states. , 2004, Cold Spring Harbor symposia on quantitative biology.

[116]  R. Young,et al.  H2AZ Is Enriched at Polycomb Complex Target Genes in ES Cells and Is Necessary for Lineage Commitment , 2008, Cell.

[117]  S. Stice,et al.  Neural differentiation of human embryonic stem cells , 2008, Journal of cellular biochemistry.

[118]  Haico van Attikum,et al.  The histone code at DNA breaks: a guide to repair? , 2005, Nature Reviews Molecular Cell Biology.

[119]  Christopher J. Nelson,et al.  Proline Isomerization of Histone H3 Regulates Lysine Methylation and Gene Expression , 2006, Cell.

[120]  Maya Schuldiner,et al.  Characterization of the expression of MHC proteins in human embryonic stem cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[121]  E. Verdin,et al.  Sirtuins: critical regulators at the crossroads between cancer and aging , 2007, Oncogene.

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

[123]  N. Benvenisty,et al.  Human Embryonic Stem Cells and Their Differentiated Derivatives Are Less Susceptible to Immune Rejection Than Adult Cells , 2006, Stem cells.

[124]  H. Sasaki,et al.  Dynamic transition of Dnmt3b expression in mouse pre- and early post-implantation embryos. , 2009, Gene expression patterns : GEP.

[125]  Tony Kouzarides,et al.  The Methyl-CpG-binding Protein MeCP2 Links DNA Methylation to Histone Methylation* , 2003, The Journal of Biological Chemistry.

[126]  D. Lees-Murdock,et al.  DNA methylation reprogramming in the germ line. , 2008, Advances in experimental medicine and biology.

[127]  Takashi Aoi,et al.  Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells , 2008, Science.

[128]  C. Costanzi,et al.  Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals , 1998, Nature.

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

[130]  Yi Zhang,et al.  Structure of the Catalytic Domain of Human DOT1L, a Non-SET Domain Nucleosomal Histone Methyltransferase , 2003, Cell.

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

[132]  W. Reik Stability and flexibility of epigenetic gene regulation in mammalian development , 2007, Nature.

[133]  S. Henikoff,et al.  Genome-scale profiling of histone H3.3 replacement patterns , 2005, Nature Genetics.

[134]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[135]  Sung-Hee Ahn,et al.  Sterile 20 Kinase Phosphorylates Histone H2B at Serine 10 during Hydrogen Peroxide-Induced Apoptosis in S. cerevisiae , 2005, Cell.

[136]  M. Bedford,et al.  Arginine methylation at a glance , 2007, Journal of Cell Science.

[137]  H. Waldmann,et al.  Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance , 2007, Proceedings of the National Academy of Sciences.

[138]  Esteban Ballestar,et al.  The impact of chromatin in human cancer: linking DNA methylation to gene silencing. , 2002, Carcinogenesis.

[139]  R. Pedersen,et al.  Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. , 1991, Development.

[140]  G. Dellgren,et al.  Immunogenicity of human embryonic stem cells , 2007, Cell and Tissue Research.

[141]  G. Churchill,et al.  Characterization of human embryonic stem cell lines by the International Stem Cell Initiative , 2007, Nature Biotechnology.

[142]  Dong Wook Han,et al.  Generation of induced pluripotent stem cells using recombinant proteins. , 2009, Cell stem cell.