The end adjusts the means: Heterochromatin remodelling during terminal cell differentiation

All cells that constitute mature tissues in an eukaryotic organism undergo a multistep process of cell differentiation. At the terminal stage of this process, cells either cease to proliferate forever or rest for a very long period of time. During terminal differentiation, most of the genes that are required for cell ‘housekeeping’ functions, such as proto-oncogenes and other cell-cycle and cell proliferation genes, become stably repressed. At the same time, nuclear chromatin undergoes dramatic morphological and structural changes at the higher-order levels of chromatin organization. These changes involve both constitutively inactive chromosomal regions (constitutive heterochromatin) and the formerly active genes that become silenced and structurally modified to form facultative heterochromatin. Here we approach terminal cell differentiation as a unique system that allows us to combine biochemical, ultrastructural and molecular genetic techniques to study the relationship between the hierarchy of chromatin higher-order structures in the nucleus and its function(s) in dynamic packing of genetic material in a form that remains amenable to regulation of gene activity and other DNA-dependent cellular processes.

[1]  G. Sudlow,et al.  Large-Scale Chromatin Unfolding and Remodeling Induced by VP16 Acidic Activation Domain , 1999, The Journal of cell biology.

[2]  D. Angelov,et al.  The histone variant macroH2A interferes with transcription factor binding and SWI/SNF nucleosome remodeling. , 2003, Molecular cell.

[3]  N. Clode,et al.  The spatial organization of centromeric heterochromatin during normal human lymphopoiesis: evidence for ontogenically determined spatial patterns. , 2003, Experimental cell research.

[4]  D. Timm,et al.  Asymmetries in the nucleosome core particle at 2.5 A resolution. , 2000, Acta crystallographica. Section D, Biological crystallography.

[5]  G. Blobel,et al.  Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. , 2005, Molecular cell.

[6]  D. Kioussis,et al.  Modulation of Heterochromatin Protein 1 Dynamics in Primary Mammalian Cells , 2003, Science.

[7]  Rachel A. Horowitz-Scherer,et al.  Chromatin Compaction by Human MeCP2 , 2003, Journal of Biological Chemistry.

[8]  Anne E Carpenter,et al.  In Vivo HP1 Targeting Causes Large-Scale Chromatin Condensation and Enhanced Histone Lysine Methylation , 2005, Molecular and Cellular Biology.

[9]  Karolin Luger,et al.  Nucleosome and chromatin fiber dynamics. , 2005, Current opinion in structural biology.

[10]  S. Grigoryev,et al.  Chromatin Structure in Granulocytes , 1998, The Journal of Biological Chemistry.

[11]  Z. Hall.  Cancer , 1906, The Hospital.

[12]  Dmitri A. Nusinow,et al.  Xist RNA and the mechanism of X chromosome inactivation. , 2002, Annual review of genetics.

[13]  S. Elgin,et al.  Long-Range Nucleosome Ordering Is Associated with Gene Silencing in Drosophila melanogaster Pericentric Heterochromatin , 2001, Molecular and Cellular Biology.

[14]  M. Koury,et al.  Nuclear substructure reorganization during late-stage erythropoiesis is selective and does not involve caspase cleavage of major nuclear substructural proteins. , 2005, Blood.

[15]  A J Koster,et al.  Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T Misteli,et al.  Protein dynamics: implications for nuclear architecture and gene expression. , 2001, Science.

[17]  T. Richmond,et al.  Chromatin fiber folding: requirement for the histone H4 N-terminal tail. , 2003, Journal of molecular biology.

[18]  D. Stocum.  Vertebrate regeneration. , 2002, Seminars in Cell and Developmental Biology.

[19]  Tatiana Nikitina,et al.  Dynamic relocation of epigenetic chromatin markers reveals an active role of constitutive heterochromatin in the transition from proliferation to quiescence. , 2004 .

[20]  J. B. Rattner,et al.  The higher-order structure of chromatin: evidence for a helical ribbon arrangement , 1984, The Journal of cell biology.

[21]  G. Palù,et al.  Gene therapy for thyroid cancer , 2004, Expert opinion on biological therapy.

[22]  S. Schreiber,et al.  Histone Variant H2A.Z Marks the 5′ Ends of Both Active and Inactive Genes in Euchromatin , 2006, Cell.

[23]  A. Bird,et al.  Molecular biology. MeCP2 repression goes nonglobal. , 2003, Science.

[24]  A. Chinnaiyan,et al.  Integrative analysis of the cancer transcriptome , 2005, Nature Genetics.

[25]  Jesse J. Lipp,et al.  Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin , 2005, Nature.

[26]  J. Hansen,et al.  Conformational dynamics of the chromatin fiber in solution: determinants, mechanisms, and functions. , 2002, Annual review of biophysics and biomolecular structure.

[27]  R. Meehan,et al.  HP1 binding to native chromatin in vitro is determined by the hinge region and not by the chromodomain , 2003, The EMBO journal.

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

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

[30]  T. Richmond,et al.  Nucleosome Arrays Reveal the Two-Start Organization of the Chromatin Fiber , 2004, Science.

[31]  Andrew J. Bannister,et al.  Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain , 2001, Nature.

[32]  Huntington F Willard,et al.  Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Karpen,et al.  Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin , 2004, Nature Structural &Molecular Biology.

[34]  Danny Reinberg,et al.  A silencing pathway to induce H 3K 9 and H 4K 20 trimethylation at constitutive heterochromatin , 2004 .

[35]  D. Tremethick,et al.  RNA interference demonstrates a novel role for H2A.Z in chromosome segregation , 2004, Nature Structural &Molecular Biology.

[36]  S. Elgin,et al.  Epigenetic Codes for Heterochromatin Formation and Silencing Rounding up the Usual Suspects , 2002, Cell.

[37]  T. Misteli,et al.  Network of Dynamic Interactions between Histone H1 and High-Mobility-Group Proteins in Chromatin , 2004, Molecular and Cellular Biology.

[38]  Jordanka Zlatanova,et al.  Chromatin fibers, one-at-a-time. , 2003, Journal of molecular biology.

[39]  T. Richmond,et al.  X-ray structure of a tetranucleosome and its implications for the chromatin fibre , 2005, Nature.

[40]  S. Elgin,et al.  The HP1 protein family: getting a grip on chromatin. , 2000, Current opinion in genetics & development.

[41]  P. Georgel,et al.  To the 30-nm chromatin fiber and beyond. , 2004, Biochimica et biophysica acta.

[42]  B. Turner,et al.  Histone acetylation and X inactivation. , 1998, Developmental genetics.

[43]  F. Crick,et al.  The structure of DNA. , 1953, Cold Spring Harbor symposia on quantitative biology.

[44]  J. Widom,et al.  New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. , 1998, Journal of molecular biology.

[45]  G S Stein,et al.  Nuclear structure-gene expression interrelationships: implications for aberrant gene expression in cancer. , 2000, Cancer research.

[46]  Emily Bernstein,et al.  RNA meets chromatin. , 2005, Genes & development.

[47]  C. Woodcock,et al.  Chromatin organization re-viewed. , 1995, Trends in cell biology.

[48]  K. Scheffzek,et al.  Splicing regulates NAD metabolite binding to histone macroH2A , 2005, Nature Structural &Molecular Biology.

[49]  Danny Reinberg,et al.  A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. , 2004, Genes & development.

[50]  E. Tanaka,et al.  Mechanisms of muscle dedifferentiation during regeneration. , 2002, Seminars in cell & developmental biology.

[51]  T. Jenuwein,et al.  Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes , 2004, The EMBO journal.

[52]  M. Sung,et al.  Sites of in vivo phosphorylation of histone H5. , 1978, Biochemistry.

[53]  S. Dimitrov,et al.  Higher-order structure of chromatin and chromosomes. , 2001, Current opinion in genetics & development.

[54]  T. Misteli,et al.  Condensed mitotic chromatin is accessible to transcription factors and chromatin structural proteins , 2005, The Journal of cell biology.

[55]  A. Leitch,et al.  Higher Levels of Organization in the Interphase Nucleus of Cycling and Differentiated Cells , 2000, Microbiology and Molecular Biology Reviews.

[56]  D. Rhodes,et al.  A method for the in vitro reconstitution of a defined "30 nm" chromatin fibre containing stoichiometric amounts of the linker histone. , 2005, Journal of molecular biology.

[57]  S. Grigoryev,et al.  Insulation of the Chicken β-Globin Chromosomal Domain from a Chromatin-Condensing Protein, MENT , 2003, Molecular and Cellular Biology.

[58]  J. Dubochet,et al.  Chromatin conformation and salt-induced compaction: three-dimensional structural information from cryoelectron microscopy , 1995, The Journal of cell biology.

[59]  Jan-Fang Cheng,et al.  Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome , 2005, Nature Genetics.

[60]  V. Ramakrishnan,et al.  Linker histone-dependent DNA structure in linear mononucleosomes. , 1996, Journal of molecular biology.

[61]  G. Setterfield,et al.  Changes in structure and composition of lymphocyte nuclei during mitogenic stimulation. , 1983, Journal of ultrastructure research.

[62]  J. O. Thomas.  Chromatin structure. , 1977, Biochemical Society symposium.

[63]  Alan P. Wolffe,et al.  Disruption of Higher-Order Folding by Core Histone Acetylation Dramatically Enhances Transcription of Nucleosomal Arrays by RNA Polymerase III , 1998, Molecular and Cellular Biology.

[64]  A. Lund,et al.  Epigenetics and cancer. , 2004, Genes & development.

[65]  K. V. van Holde,et al.  Linker DNA accessibility in chromatin fibers of different conformations: a reevaluation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[66]  A. Bird,et al.  MeCP2 Repression Goes Nonglobal , 2003, Science.

[67]  N. Gilbert,et al.  Distinctive higher-order chromatin structure at mammalian centromeres , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[68]  M. Groudine,et al.  Nuclear relocation of a transactivator subunit precedes target gene activation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[69]  H. Martinson,et al.  Nucleosome spacing is compressed in active chromatin domains of chick erythroid cells. , 1992, Biochemistry.

[70]  J. Whisstock,et al.  Inhibitory Activity of a Heterochromatin-associated Serpin (MENT) against Papain-like Cysteine Proteinases Affects Chromatin Structure and Blocks Cell Proliferation* , 2002, Journal of Biological Chemistry.

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

[72]  J. Wong,et al.  Relationship between Histone H3 Lysine 9 Methylation, Transcription Repression, and Heterochromatin Protein 1 Recruitment , 2005, Molecular and Cellular Biology.

[73]  Matthias Merkenschlager,et al.  Association of Transcriptionally Silent Genes with Ikaros Complexes at Centromeric Heterochromatin , 1997, Cell.

[74]  A Klug,et al.  Involvement of histone H1 in the organization of the nucleosome and of the salt-dependent superstructures of chromatin , 1979, The Journal of cell biology.

[75]  S. Galande,et al.  Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndrome. , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[76]  S. Grigoryev,et al.  Keeping fingers crossed: heterochromatin spreading through interdigitation of nucleosome arrays , 2004, FEBS letters.

[77]  K. Luger,et al.  Crystal structure of a nucleosome core particle containing the variant histone H2A.Z , 2000, Nature Structural Biology.

[78]  Sue Biggins,et al.  Histone variants: deviants? , 2005, Genes & development.

[79]  D A Agard,et al.  The three-dimensional architecture of chromatin in situ: electron tomography reveals fibers composed of a continuously variable zig-zag nucleosomal ribbon , 1994, The Journal of cell biology.

[80]  J. Pehrson,et al.  Evolutionary conservation of histone macroH2A subtypes and domains. , 1998, Nucleic acids research.

[81]  Nick Gilbert,et al.  Chromatin Architecture of the Human Genome Gene-Rich Domains Are Enriched in Open Chromatin Fibers , 2004, Cell.

[82]  J. A. Sanchez,et al.  Efficient reactivation of Xenopus erythrocyte nuclei in Xenopus egg extracts. , 1995, Journal of cell science.

[83]  A. Fisher,et al.  Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. , 1999, Molecular cell.

[84]  M. Groudine,et al.  Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human beta-globin locus. , 2000, Genes & development.

[85]  I. Callebaut,et al.  Domain-specific Interactions of Human HP1-type Chromodomain Proteins and Inner Nuclear Membrane Protein LBR* , 1997, The Journal of Biological Chemistry.

[86]  Prim B. Singh,et al.  HP1: facts, open questions, and speculation. , 2002, Journal of structural biology.

[87]  J. Köhrle,et al.  Retinoic acid redifferentiation therapy for thyroid cancer. , 2000, Thyroid : official journal of the American Thyroid Association.

[88]  J. Hansen,et al.  Reversible oligonucleosome self-association: dependence on divalent cations and core histone tail domains. , 1996, Biochemistry.

[89]  H. Xu,et al.  DNA replication in quiescent cell nuclei: regulation by the nuclear envelope and chromatin structure. , 1999, Molecular biology of the cell.

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

[91]  T. Magnuson,et al.  H1 Linker Histones Are Essential for Mouse Development and Affect Nucleosome Spacing In Vivo , 2003, Molecular and Cellular Biology.

[92]  Michal Kozubek,et al.  Nuclear structure and gene activity in human differentiated cells. , 2002, Journal of structural biology.

[93]  D. Landsman,et al.  The Biochemical and Phenotypic Characterization of Hho1p, the Putative Linker Histone H1 of Saccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[94]  J. Ausió,et al.  Modulation of Chromatin Folding by Histone Acetylation (*) , 1995, The Journal of Biological Chemistry.

[95]  R. Dilão,et al.  Spatial associations of centromeres in the nuclei of hematopoietic cells: evidence for cell-type-specific organizational patterns. , 2000, Blood.

[96]  S. Jacobs,et al.  Structure of HP1 Chromodomain Bound to a Lysine 9-Methylated Histone H3 Tail , 2002, Science.

[97]  R. Bouillon,et al.  A structural basis for the unique binding features of the human vitamin D-binding protein , 2002, Nature Structural Biology.

[98]  J. Bednar,et al.  MENT, a Heterochromatin Protein That Mediates Higher Order Chromatin Folding, Is a New Serpin Family Member* , 1999, The Journal of Biological Chemistry.

[99]  David T. Brown.  Histone H1 and the dynamic regulation of chromatin function. , 2003, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[100]  S. Smale,et al.  Down-regulation of TDT transcription in CD4(+)CD8(+) thymocytes by Ikaros proteins in direct competition with an Ets activator. , 2001, Genes & development.

[101]  S. Grigoryev.  Higher-order folding of heterochromatin: protein bridges span the nucleosome arrays. , 2001, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[102]  Tom Misteli,et al.  Maintenance of Stable Heterochromatin Domains by Dynamic HP1 Binding , 2003, Science.

[103]  J. Hansen,et al.  Hybrid trypsinized nucleosomal arrays: identification of multiple functional roles of the H2A/H2B and H3/H4 N-termini in chromatin fiber compaction. , 1997, Biochemistry.

[104]  J. Whisstock,et al.  Role of the M-loop and Reactive Center Loop Domains in the Folding and Bridging of Nucleosome Arrays by MENT* , 2003, Journal of Biological Chemistry.

[105]  J. Widom.  Physicochemical studies of the folding of the 100 A nucleosome filament into the 300 A filament. Cation dependence. , 1986, Journal of molecular biology.

[106]  T. Graf,et al.  GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. , 1995, Genes & development.

[107]  V. Corces,et al.  The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin. , 2005, Genes & development.

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

[109]  Thomas Cremer,et al.  Methyl CpG–binding proteins induce large-scale chromatin reorganization during terminal differentiation , 2005, The Journal of cell biology.

[110]  R. Ghirlando,et al.  Physical properties of a genomic condensed chromatin fragment. , 2004, Journal of molecular biology.

[111]  Hiten D. Madhani,et al.  Conserved Histone Variant H2A.Z Protects Euchromatin from the Ectopic Spread of Silent Heterochromatin , 2003, Cell.

[112]  D. E. Olins,et al.  Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huët anomaly) , 2002, Nature Genetics.

[113]  M. Kozubek,et al.  Methylation of histones in myeloid leukemias as a potential marker of granulocyte abnormalities , 2005, Journal of leukocyte biology.

[114]  Dirk Schübeler,et al.  Nuclear compartmentalization and gene activity , 2000, Nature Reviews Molecular Cell Biology.

[115]  A. Ladurner.  Inactivating chromosomes: a macro domain that minimizes transcription. , 2003, Molecular cell.

[116]  M. Schmid,et al.  Experimental condensation inhibition in constitutive and facultative heterochromatin of mammalian chromosomes , 2000, Cytogenetic and Genome Research.

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

[118]  G. Almouzni,et al.  HP1 and the dynamics of heterochromatin maintenance , 2004, Nature Reviews Molecular Cell Biology.

[119]  Ernest D Laue,et al.  Structural basis of HP1/PXVXL motif peptide interactions and HP1 localisation to heterochromatin , 2004, The EMBO journal.

[120]  J. Hansen,et al.  Chromatin architectural proteins , 2006, Chromosome Research.

[121]  T. Sugimura,et al.  Genetic and epigenetic alterations in carcinogenesis. , 2000, Mutation research.

[122]  A. Fisher,et al.  Dynamic assembly of silent chromatin during thymocyte maturation , 2004, Nature Genetics.

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

[124]  T. Richmond,et al.  The structure of DNA in the nucleosome core , 2003, Nature.

[125]  G. Almouzni,et al.  Mouse centric and pericentric satellite repeats form distinct functional heterochromatin , 2004, The Journal of cell biology.

[126]  James Allan,et al.  Formation of facultative heterochromatin in the absence of HP1 , 2003, The EMBO journal.

[127]  S. Baylin,et al.  Dnmt3a and Dnmt3b Are Transcriptional Repressors That Exhibit Unique Localization Properties to Heterochromatin* , 2001, The Journal of Biological Chemistry.

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

[129]  K. Luger,et al.  Structural Characterization of the Histone Variant macroH2A , 2005, Molecular and Cellular Biology.