Constitutive heterochromatin formation and transcription in mammals

Constitutive heterochromatin, mainly formed at the gene-poor regions of pericentromeres, is believed to ensure a condensed and transcriptionally inert chromatin conformation. Pericentromeres consist of repetitive tandem satellite repeats and are crucial chromosomal elements that are responsible for accurate chromosome segregation in mitosis. The repeat sequences are not conserved and can greatly vary between different organisms, suggesting that pericentromeric functions might be controlled epigenetically. In this review, we will discuss how constitutive heterochromatin is formed and maintained at pericentromeres in order to ensure their integrity. We will describe the biogenesis and the function of main epigenetic pathways that are involved and how they are interconnected. Interestingly, recent findings suggest that alternative pathways could substitute for well-established pathways when disrupted, suggesting that constitutive heterochromatin harbors much more plasticity than previously assumed. In addition, despite of the heterochromatic nature of pericentromeres, there is increasing evidence for active and regulated transcription at these loci, in a multitude of organisms and under various biological contexts. Thus, in the second part of this review, we will address this relatively new aspect and discuss putative functions of pericentromeric expression.

[1]  T. Jenuwein,et al.  Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition. , 2013, Molecular cell.

[2]  S. E. Mitchell,et al.  Pericentric and centromeric transcription: a perfect balance required , 2012, Chromosome Research.

[3]  C. Allis,et al.  Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling. , 2007, Trends in molecular medicine.

[4]  K. Rohr,et al.  Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin. , 2013, Genes & development.

[5]  P. Dollé,et al.  Transcripts from opposite strands of γ satellite DNA are differentially expressed during mouse development , 1995, Mammalian Genome.

[6]  D. Oxley,et al.  Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. , 2011, Molecular cell.

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

[8]  Yi Zhang,et al.  Regulation of histone methylation by demethylimination and demethylation , 2007, Nature Reviews Molecular Cell Biology.

[9]  L. Peichl,et al.  LBR and Lamin A/C Sequentially Tether Peripheral Heterochromatin and Inversely Regulate Differentiation , 2013, Cell.

[10]  F. Collins,et al.  Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[11]  C. Allis,et al.  Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres , 2010, Proceedings of the National Academy of Sciences.

[12]  K. Muegge,et al.  Lsh, a modulator of CpG methylation, is crucial for normal histone methylation , 2003, The EMBO journal.

[13]  E. Selker,et al.  A histone H3 methyltransferase controls DNA methylation in Neurospora crassa , 2001, Nature.

[14]  V. Ogryzko,et al.  Dualistic function of Daxx at centromeric and pericentromeric heterochromatin in normal and stress conditions , 2012, Nucleus.

[15]  Martin Radolf,et al.  The profile of repeat‐associated histone lysine methylation states in the mouse epigenome , 2005, The EMBO journal.

[16]  S. Riva,et al.  Structural and functional characterization of noncoding repetitive RNAs transcribed in stressed human cells. , 2005, Molecular biology of the cell.

[17]  D. Reinberg,et al.  Chromatin structure and the inheritance of epigenetic information , 2010, Nature Reviews Genetics.

[18]  James A. Birchler,et al.  Heterochromatic Silencing and HP1 Localization in Drosophila Are Dependent on the RNAi Machinery , 2004, Science.

[19]  S. Gygi,et al.  HP1 proteins form distinct complexes and mediate heterochromatic gene silencing by nonoverlapping mechanisms. , 2008, Molecular cell.

[20]  A. Dejean,et al.  Coordinated methyl and RNA binding is required for heterochromatin localization of mammalian HP1α , 2002, EMBO reports.

[21]  N. Enukashvily,et al.  Mammalian satellite DNA: a speaking dumb. , 2013, Advances in protein chemistry and structural biology.

[22]  D. Reinberg,et al.  NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs , 2007, Oncogene.

[23]  K. Ekwall,et al.  Epigenetics: heterochromatin meets RNAi , 2009, Cell Research.

[24]  Jiming Jiang,et al.  The Centromeric Retrotransposons of Rice Are Transcribed and Differentially Processed by RNA Interference , 2007, Genetics.

[25]  R. Poot,et al.  An ACF1–ISWI chromatin-remodeling complex is required for DNA replication through heterochromatin , 2002, Nature Genetics.

[26]  Stephan Sauer,et al.  The reorganisation of constitutive heterochromatin in differentiating muscle requires HDAC activity. , 2005, Experimental cell research.

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

[28]  T. Jenuwein,et al.  Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component , 2002, Nature Genetics.

[29]  C. Ghigna,et al.  Transcription of Satellite III non-coding RNAs is a general stress response in human cells , 2007, Nucleic Acids Research.

[30]  J. Birchler,et al.  Making noise about silence: repression of repeated genes in animals. , 2000, Current opinion in genetics & development.

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

[32]  M. Rocchi,et al.  Human chromosomes 9, 12, and 15 contain the nucleation sites of stress-induced nuclear bodies. , 2002, Molecular biology of the cell.

[33]  W. Reik,et al.  Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation. , 2014, Molecular cell.

[34]  M. Blasco,et al.  TERRA transcripts are bound by a complex array of RNA-binding proteins. , 2010, Nature communications.

[35]  Fred H. Gage,et al.  BRCA1 tumor suppression occurs via heterochromatin mediated silencing , 2011, Nature.

[36]  T. Bruxner,et al.  An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. Malashicheva,et al.  Satellite DNA Spatial Localization and Transcriptional Activity in Mouse Embryonic E-14 and IOUD2 Stem Cells , 2009, Cytogenetic and Genome Research.

[38]  C. Francastel,et al.  Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

[40]  D A Sinclair,et al.  Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. , 1997, Science.

[41]  G. Längst,et al.  NoRC—a novel member of mammalian ISWI‐containing chromatin remodeling machines , 2001, The EMBO journal.

[42]  K. Luger,et al.  Short Article H2A.Z Alters the Nucleosome Surface to Promote HP1-Mediated Chromatin Fiber Folding , 2004 .

[43]  T. James,et al.  Identification of a nonhistone chromosomal protein associated with heterochromatin in Drosophila melanogaster and its gene , 1986, Molecular and cellular biology.

[44]  R. Steward,et al.  Functional Characterization of the Drosophila Hmt4-20/Suv4-20 Histone Methyltransferase , 2008, Genetics.

[45]  A. Iafrate,et al.  Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers , 2011, Science.

[46]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[47]  T. Volpe,et al.  RNA interference and heterochromatin assembly. , 2011, Cold Spring Harbor perspectives in biology.

[48]  R. Morimoto,et al.  HSF1 transcription factor concentrates in nuclear foci during heat shock: relationship with transcription sites. , 1997, Journal of cell science.

[49]  M. Asashima,et al.  Mouse homolog of SALL1, a causative gene for Townes–Brocks syndrome, binds to A/T‐rich sequences in pericentric heterochromatin via its C‐terminal zinc finger domains , 2007, Genes to cells : devoted to molecular & cellular mechanisms.

[50]  G. Maul,et al.  Heterochromatin and ND10 are cell-cycle regulated and phosphorylation-dependent alternate nuclear sites of the transcription repressor Daxx and SWI/SNF protein ATRX , 2004, Journal of Cell Science.

[51]  B. Sullivan,et al.  Genomic size of CENP-A domain is proportional to total alpha satellite array size at human centromeres and expands in cancer cells , 2011, Chromosome Research.

[52]  E. Greer,et al.  Histone methylation: a dynamic mark in health, disease and inheritance , 2012, Nature Reviews Genetics.

[53]  R. Martienssen,et al.  The role of RNA interference in heterochromatic silencing , 2004, Nature.

[54]  P. Molloy,et al.  DNA hypomethylation and human diseases. , 2007, Biochimica et biophysica acta.

[55]  D. Moazed.  Enzymatic activities of Sir2 and chromatin silencing. , 2001, Current opinion in cell biology.

[56]  K. Mitsuya,et al.  The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA , 2007, Nature.

[57]  Karl Mechtler,et al.  Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins , 2001, Nature.

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

[59]  J A Eisen,et al.  Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. , 1995, Nucleic acids research.

[60]  J. Martens,et al.  Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. , 2003, Molecular cell.

[61]  S. Riva,et al.  Transcriptional activation of a constitutive heterochromatic domain of the human genome in response to heat shock. , 2003, Molecular biology of the cell.

[62]  M. Vigneron,et al.  Stress-induced transcription of satellite III repeats , 2004, The Journal of cell biology.

[63]  D. Reinberg,et al.  The Polycomb complex PRC2 and its mark in life , 2011, Nature.

[64]  B. Sullivan,et al.  Structural and functional dynamics of human centromeric chromatin. , 2006, Annual review of genomics and human genetics.

[65]  R. Festenstein,et al.  Unravelling heterochromatin: competition between positive and negative factors regulates accessibility. , 2002, Trends in genetics : TIG.

[66]  T. Jenuwein,et al.  Di-methyl H4 Lysine 20 Targets the Checkpoint Protein Crb2 to Sites of DNA Damage* , 2008, Journal of Biological Chemistry.

[67]  M. Ehrlich,et al.  RNAPol-ChIP analysis of transcription from FSHD-linked tandem repeats and satellite DNA. , 2007, Biochimica et biophysica acta.

[68]  R. E. Esposito,et al.  A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA , 1989, Cell.

[69]  K. McManus,et al.  Dynamic Changes in Histone H3 Lysine 9 Methylations , 2006, Journal of Biological Chemistry.

[70]  D. Gilbert,et al.  Proliferation-dependent and cell cycle–regulated transcription of mouse pericentric heterochromatin , 2007, The Journal of cell biology.

[71]  Yoichi Shinkai,et al.  SET Domain-containing Protein, G9a, Is a Novel Lysine-preferring Mammalian Histone Methyltransferase with Hyperactivity and Specific Selectivity to Lysines 9 and 27 of Histone H3* , 2001, The Journal of Biological Chemistry.

[72]  G. Biamonti.  Nuclear stress bodies: a heterochromatin affair? , 2004, Nature Reviews Molecular Cell Biology.

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

[74]  T. Jenuwein,et al.  Mammalian Su(var) genes in chromatin control. , 2010, Annual review of cell and developmental biology.

[75]  Caroline Jolly,et al.  A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules , 2004, Journal of Cell Science.

[76]  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 .

[77]  H. Kato,et al.  KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state , 2008, Cell cycle.

[78]  I. Grummt,et al.  The chromatin remodelling complex NoRC safeguards genome stability by heterochromatin formation at telomeres and centromeres , 2013, EMBO reports.

[79]  H. Tapiero,et al.  RNA replication by nuclear satellite DNA in different mouse cells. , 1968, Biochemical and biophysical research communications.

[80]  Toshiyuki Shimizu,et al.  Epigenetic Control of rDNA Loci in Response to Intracellular Energy Status , 2008, Cell.

[81]  M. Westphal,et al.  Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. , 1999, Cancer genetics and cytogenetics.

[82]  K. Muegge.  Lsh, a guardian of heterochromatin at repeat elements. , 2005, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[83]  M. Zofall,et al.  Cell cycle control of centromeric repeat transcription and heterochromatin assembly , 2008, Nature.

[84]  M. Oshimura,et al.  Dicer is essential for formation of the heterochromatin structure in vertebrate cells , 2004, Nature Cell Biology.

[85]  Dimos Gaidatzis,et al.  Step-Wise Methylation of Histone H3K9 Positions Heterochromatin at the Nuclear Periphery , 2012, Cell.

[86]  P. Andrews,et al.  Impaired replication elongation in Tetrahymena mutants deficient in histone H3 Lys 27 monomethylation. , 2013, Genes & development.

[87]  H. Kimura,et al.  Human POGZ modulates dissociation of HP1α from mitotic chromosome arms through Aurora B activation , 2010, Nature Cell Biology.

[88]  Karl Mechtler,et al.  Loss of the Suv39h Histone Methyltransferases Impairs Mammalian Heterochromatin and Genome Stability , 2001, Cell.

[89]  P. Ridgway,et al.  Pericentric heterochromatin becomes enriched with H2A.Z during early mammalian development , 2003, The EMBO journal.

[90]  A. Hamiche,et al.  The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. , 2010, Genes & development.

[91]  F. Berger,et al.  A transcriptomic analysis of human centromeric and pericentric sequences in normal and tumor cells , 2009, Nucleic acids research.

[92]  Xiaojun Ding,et al.  Histone methyltransferase G9a contributes to H3K27 methylation in vivo , 2011, Cell Research.

[93]  C. Ghigna,et al.  RNA recognition motif 2 directs the recruitment of SF2/ASF to nuclear stress bodies. , 2004, Nucleic acids research.

[94]  A. Probst,et al.  A strand-specific burst in transcription of pericentric satellites is required for chromocenter formation and early mouse development. , 2010, Developmental cell.

[95]  G. Almouzni,et al.  The HP1α–CAF1–SetDB1‐containing complex provides H3K9me1 for Suv39‐mediated K9me3 in pericentric heterochromatin , 2009, EMBO reports.

[96]  G. Karpen,et al.  H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability , 2007, Nature Cell Biology.

[97]  D. Moazed.  Mechanisms for the Inheritance of Chromatin States , 2011, Cell.

[98]  Stephen P. Fox,et al.  Lsh, an epigenetic guardian of repetitive elements. , 2004, Nucleic acids research.

[99]  R. Donev,et al.  Human chromosome 1 satellite 3 DNA is decondensed, demethylated and transcribed in senescent cells and in A431 epithelial carcinoma cells , 2007, Cytogenetic and Genome Research.

[100]  M. Callanan,et al.  The secret message of heterochromatin: new insights into the mechanisms and function of centromeric and pericentric repeat sequence transcription. , 2009, The International journal of developmental biology.

[101]  R. Morimoto,et al.  In vivo binding of active heat shock transcription factor 1 to human chromosome 9 heterochromatin during stress , 2002, The Journal of cell biology.

[102]  T. Eickbush,et al.  Heterochromatin Formation Promotes Longevity and Represses Ribosomal RNA Synthesis , 2012, PLoS genetics.

[103]  M. Fussenegger,et al.  The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats , 2010, The EMBO journal.

[104]  Andrew J. Bannister,et al.  Regulation of chromatin by histone modifications , 2011, Cell Research.

[105]  Giacomo Cavalli,et al.  Cellular memory and dynamic regulation of polycomb group proteins. , 2006, Current opinion in cell biology.

[106]  T. Jenuwein,et al.  A transcription factor–based mechanism for mouse heterochromatin formation , 2012, Nature Structural &Molecular Biology.

[107]  T. Sugiyama,et al.  RITS acts in cis to promote RNA interference–mediated transcriptional and post-transcriptional silencing , 2004, Nature Genetics.

[108]  S. Elgin,et al.  Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[109]  F. Portillo,et al.  Switching On-Off Snail: LOXL2 Versus GSK3? , 2005 .

[110]  Mitsuhiro Nakamura,et al.  Cell cycle-dependent accumulation of histone H3.3 and euchromatic histone modifications in pericentromeric heterochromatin in response to a decrease in DNA methylation levels. , 2010, Experimental cell research.

[111]  S. Orkin,et al.  PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos , 2008, Nature Genetics.

[112]  J. Walter,et al.  Dissecting the role of H3K64me3 in mouse pericentromeric heterochromatin , 2013, Nature Communications.

[113]  D. Higgs,et al.  ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. , 1996, Human molecular genetics.

[114]  T. Mitchison,et al.  Vertebrate Shugoshin Links Sister Centromere Cohesion and Kinetochore Microtubule Stability in Mitosis , 2004, Cell.

[115]  A. Gartner,et al.  Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation , 2009, Molecules and cells.

[116]  R. Kuick,et al.  ICF, An Immunodeficiency Syndrome: DNA Methyltransferase 3B Involvement, Chromosome Anomalies, and Gene Dysregulation , 2008, Autoimmunity.

[117]  D. Reinberg,et al.  Prdm3 and Prdm16 are H3K9me1 Methyltransferases Required for Mammalian Heterochromatin Integrity , 2012, Cell.

[118]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[119]  J. P. Jackson,et al.  Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase , 2002, Nature.

[120]  Ming-Ming Zhou,et al.  Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing , 2008, Nature Structural &Molecular Biology.

[121]  Sheng‐Chung Lee,et al.  WDHD1 modulates the post-transcriptional step of the centromeric silencing pathway , 2011, Nucleic acids research.

[122]  Andrew J. Bannister,et al.  Heterochromatin formation in the mouse embryo requires critical residues of the histone variant H3.3 , 2010, Nature Cell Biology.

[123]  A. Pombo,et al.  Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[124]  T. Möröy,et al.  Gfi1b alters histone methylation at target gene promoters and sites of γ‐satellite containing heterochromatin , 2006, The EMBO journal.

[125]  K. Luo,et al.  SIR2 and SIR4 interactions differ in core and extended telomeric heterochromatin in yeast. , 1997, Genes & development.

[126]  A. Vaquero,et al.  Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. , 2011, Molecular cell.

[127]  W. Flamm,et al.  Some properties of the single strands isolated from the DNA of the nuclear satellite of the mouse (Mus musculus). , 1969, Journal of molecular biology.

[128]  Y. Gruenbaum,et al.  Hutchinson–Gilford progeria syndrome through the lens of transcription , 2013, Aging cell.

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

[130]  S. Um,et al.  SIRT1: roles in aging and cancer. , 2008, BMB reports.

[131]  F. Ledeist,et al.  An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. , 1993, Human molecular genetics.

[132]  Hongtao Yu,et al.  Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[133]  P. Wade,et al.  The Mi-2/NuRD complex associates with pericentromeric heterochromatin during S phase in rapidly proliferating lymphoid cells , 2009, Chromosoma.