Key Points
-
Protein domains that bind ('read') histones bearing specific post-translational modifications are frequently physically coupled to enzymes that catalyse the addition ('writer') or removal ('eraser') of histone modifications.
-
Transcription of heterochromatin produces noncoding RNAs that provide recruitment platforms for chromatin-modifying enzymes.
-
The processes that initiate heterochromatin establishment are separable from those that mediate its maintenance. Once initiated, heterochromatin can engulf neighbouring chromatin, but spreading is limited by multiple mechanisms.
-
Reader–writer coupling suggests that heterochromatin can direct its persistence through replication and cell division independently of nucleic acid cues. Experimental tests suggest that heterochromatin heritability is strongly countered by opposing activities.
-
Heterochromatin suppresses chromosome rearrangements by directing specific avenues of repair within repetitive DNA. Heterochromatin also promotes accurate chromosome segregation.
-
Domains of heterochromatin limit the repertoire of expressed genes in differentiated cells and inhibit their reprogramming to pluripotent cells. A variety of human diseases are affected by the alterations in the ability to form, or the distribution of, heterochromatin.
Abstract
Heterochromatin is a key architectural feature of eukaryotic chromosomes, which endows particular genomic domains with specific functional properties. The capacity of heterochromatin to restrain the activity of mobile elements, isolate DNA repair in repetitive regions and ensure accurate chromosome segregation is crucial for maintaining genomic stability. Nucleosomes at heterochromatin regions display histone post-translational modifications that contribute to developmental regulation by restricting lineage-specific gene expression. The mechanisms of heterochromatin establishment and of heterochromatin maintenance are separable and involve the ability of sequence-specific factors bound to nascent transcripts to recruit chromatin-modifying enzymes. Heterochromatin can spread along the chromatin from nucleation sites. The propensity of heterochromatin to promote its own spreading and inheritance is counteracted by inhibitory factors. Because of its importance for chromosome function, heterochromatin has key roles in the pathogenesis of various human diseases. In this Review, we discuss conserved principles of heterochromatin formation and function using selected examples from studies of a range of eukaryotes, from yeast to human, with an emphasis on insights obtained from unicellular model organisms.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zhou, C. Y., Johnson, S. L., Gamarra, N. I. & Narlikar, G. J. Mechanisms of ATP-dependent chromatin remodeling motots. Annu. Rev. Biophys. 45, 153–181 (2016).
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
Tschiersch, B. et al. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J. 13, 3822 (1994).
Eissenberg, J. C. et al. Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 87, 9923–9927 (1990).
Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).
Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).
Lorentz, A., Ostermann, K., Fleck, O. & Schmidt, H. Switching gene swi6, involved in repression of silent mating-type loci in fission yeast, encodes a homologue of chromatin-associated proteins from Drosophila and mammals. Gene 143, 139–143 (1994).
Allshire, R. C., Nimmo, E. R., Ekwall, K., Javerzat, J. P. & Cranston, G. Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. Genes Dev. 9, 218–233 (1995).
Thon, G. & Verhein-Hansen, J. Four chromo-domain proteins of Schizosaccharomyces pombe differentially repress transcription at various chromosomal locations. Genetics 155, 551–568 (2000).
Klar, A. J. & Bonaduce, M. J. swi6, a gene required for mating-type switching, prohibits meiotic recombination in the mat2-mat3 “cold spot” of fission yeast. Genetics 129, 1033–1042 (1991).
Lorentz, A., Heim, L. & Schmidt, H. The switching gene swi6 affects recombination and gene expression in the mating-type region of Schizosaccharomyces pombe. Mol. Gen. Genet. 233, 436–442 (1992).
Ekwall, K. & Ruusala, T. Mutations in rik1, clr2, clr3 and clr4 genes asymmetrically derepress the silent mating-type loci in fission yeast. Genetics 136, 53–64 (1994).
Thon, G., Cohen, A. & Klar, A. J. Three additional linkage groups that repress transcription and meiotic recombination in the mating-type region of Schizosaccharomyces pombe. Genetics 138, 29–38 (1994).
Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).
Jackson, J. P., Lindroth, A. M., Cao, X. & Jacobsen, S. E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).
Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).
Hashimshony, T., Zhang, J., Keshet, I., Bustin, M. & Cedar, H. The role of DNA methylation in setting up chromatin structure during development. Nat. Genet. 34, 187–192 (2003).
Kueng, S., Oppikofer, M. & Gasser, S. M. SIR proteins and the assembly of silent chromatin in budding yeast. Ann. Rev. Genet. 47, 275–306 (2013).
Rusche, L. N., Kirchmaier, A. L. & Rine, J. The establishment, inheritance, and function of silenced chromatin in Saccharomyces cerevisiae. Ann. Rev. Biochem. 72, 481–516 (2003).
Armache, K. J., Garlick, J. D., Canzio, D., Narlikar, G. J. & Kingston, R. E. Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 A resolution. Science 334, 977–982 (2011).
Hanson, S. J. & Wolfe, K. H. An evolutionary perspective on yeast mating-type switching. Genetics 206, 9–32 (2017).
Ekwall, K. et al. Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function. J. Cell Sci. 109, 2637–2648 (1996).
Maison, C. et al. Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nat. Genet. 30, 329–334 (2002).
Sadaie, M., Iida, T., Urano, T. & Nakayama, J. A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. EMBO J. 23, 3825–3835 (2004).
Brasher, S. V. et al. The structure of mouse HP1 suggests a unique mode of single peptide recognition by the shadow chromo domain dimer. EMBO J. 19, 1587–1597 (2000).
Cowieson, N. P., Partridge, J. F., Allshire, R. C. & McLaughlin, P. J. Dimerisation of a chromo shadow domain and distinctions from the chromodomain as revealed by structural analysis. Curr. Biol. 10, 517–525 (2000).
Motamedi, M. R. et al. HP1 proteins form distinct complexes and mediate heterochromatic gene silencing by nonoverlapping mechanisms. Mol. Cell 32, 778–790 (2008).
Fischer, T. et al. Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast. Proc. Natl Acad. Sci. USA 106, 8998–9003 (2009).
Garcia, J. F., Dumesic, P. A., Hartley, P. D., El-Samad, H. & Madhani, H. D. Combinatorial, site-specific requirement for heterochromatic silencing factors in the elimination of nucleosome-free regions. Genes Dev. 24, 1758–1771 (2010).
Creamer, K. M. et al. The Mi-2 homolog Mit1 actively positions nucleosomes within heterochromatin to suppress transcription. Mol. Cell. Biol. 34, 2046–2061 (2014).
Canzio, D. et al. A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly. Nature 496, 377–381 (2013).
Cao, R. et al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298, 1039–1043 (2002).
Müller, J. et al. Histone methyltransferase activity of a Drosophila polycomb group repressor complex. Cell 111, 197–208 (2002).
Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).
Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16, 2893–2905 (2002).
Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003).
Margueron, R. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009).
Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).
Kloc, A., Zaratiegui, M., Nora, E. & Martienssen, R. RNA interference guides histone modification during the S phase of chromosomal replication. Curr. Biol. 18, 490–495 (2008).
Chen, E. S. et al. Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature 451, 734–737 (2008).
Lu, J. & Gilbert, D. M. Proliferation-dependent and cell cycle regulated transcription of mouse pericentric heterochromatin. J. Cell Biol. 179, 411–421 (2007).
Reinhart, B. & Bartel, D. P. Small RNAs correspond to centromere heterochromatic repeats. Science 13, 1831 (2002).
Motamedi, M. R. et al. Two RNAi complexes, RITS and RDRC, physically interact and localize to noncoding centromeric RNAs. Cell 119, 789–802 (2004).
Bayne, E. H. et al. Stc1: a critical link between RNAi and chromatin modification required for heterochromatin integrity. Cell 140, 666–677 (2010).
Zhang, K., Mosch, K., Fischle, W. & Grewal, S. I. Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin. Nat. Struct. Mol. Biol. 15, 381–388 (2008).
Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).
Buhler, M., Verdel, A. & Moazed, D. Tethering RITS to a nascent transcript initiates RNAi- and heterochromatin-dependent gene silencing. Cell 125, 873–886 (2006).
Gerace, E. L., Halic, M. & Moazed, D. The methyltransferase activity of Clr4Suv39h triggers RNAi independently of histone H3K9 methylation. Mol. Cell 39, 360–372 (2010).
Jain, R., Iglesias, N. & Moazed, D. Distinct functions of argonaute slicer in siRNA maturation and heterochromatin formation. Mol. Cell 63, 191–205 (2016).
Colmenares, S. U., Buker, S. M., Buhler, M., Dlakic, M. & Moazed, D. Coupling of double-stranded RNA synthesis and siRNA generation in fission yeast RNAi. Mol. Cell 27, 449–461 (2007).
Kato, H. et al. RNA polymerase II is required for RNAi-dependent heterochromatin assembly. Science 309, 467–469 (2005).
Djupedal, I. et al. RNA Pol II subunit Rpb7 promotes centromeric transcription and RNAi-directed chromatin silencing. Genes Dev. 19, 2301–2306 (2005).
Hong, E. J., Villen, J., Gerace, E. L., Gygi, S. P. & Moazed, D. A cullin E3 ubiquitin ligase complex associates with Rik1 and the Clr4 histone H3-K9 methyltransferase and is required for RNAi-mediated heterochromatin formation. RNA Biol. 2, 106–111 (2005).
Horn, P. J., Bastie, J. N. & Peterson, C. L. A. Rik1-associated, cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation. Genes Dev. 19, 1705–1714 (2005).
Jia, S., Kobayashi, R. & Grewal, S. I. Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin. Nat. Cell Biol. 7, 1007–1013 (2005).
Sugiyama, T., Cam, H., Verdel, A., Moazed, D. & Grewal, S. I. RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production. Proc. Natl Acad. Sci. USA 102, 152–157 (2005).
Partridge, J. F., Borgstrøm, B. & Allshire, R. Distinct protein interaction domains and protein spreading in a complex centromere. Genes Dev. 14, 783–791 (2000).
Cam, H. P. et al. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nat. Genet. 37, 809–819 (2005).
Rougemaille, M. et al. Ers1 links HP1 to RNAi. Proc. Natl Acad. Sci. USA 109, 11258–11263 (2012).
Hayashi, A. et al. Heterochromatin protein 1 homologue Swi6 acts in concert with Ers1 to regulate RNAi-directed heterochromatin assembly. Proc. Natl Acad. Sci. USA 109, 6159–6164 (2012).
Rougemaille, M., Shankar, S., Braun, S., Rowley, M. & Madhani, H. D. Ers1, a rapidly diverging protein essential for RNA interference-dependent heterochromatic silencing in Schizosaccharomyces pombe. J. Biol. Chem. 283, 25770–25773 (2008).
Wierzbicki, A. T., Ream, T. S., Haag, J. R. & Pikaard, C. S. RNA polymerase V transcription guides ARGONAUTE4 to chromatin. Nat. Genet. 41, 630–634 (2009).
Zhong, X. et al. Molecular mechanism of action of plant DRM de novo DNA methyltransferases. Cell 157, 1050–1060 (2014).
Liu, Z. W. et al. The SET domain proteins SUVH2 and SUVH9 are required for Pol V occupancy at RNA-directed DNA methylation loci. PLoS Genet. 10, e1003948 (2014).
Herr, A. J., Jensen, M. B., Dalmay, T. & Baulcombe, D. C. RNA polymerase IV directs silencing of endogenous DNA. Science 308, 118–120 (2005).
Blevins, T. et al. Identification of Pol IV and RDR2-dependent precursors of 24 nt siRNAs guiding de novo DNA methylation in Arabidopsis. eLife 4, e09591 (2015).
Zhai, J. et al. A one precursor one siRNA model for Pol IV-dependent siRNA biogenesis. Cell 163, 445–455 (2015).
Zhang, H. et al. DTF1 is a core component of RNA-directed DNA methylation and may assist in the recruitment of Pol IV. Proc. Natl Acad. Sci. USA 110, 8290–8295 (2013). References 67 and 68 show that short double-stranded RNA precursors generated by Pol IV and RNA-dependent polymerase 2 produce a single siRNA duplex through the activity of the Dicer Dcl3.
Law, J. A. et al. Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1. Nature 498, 385–389 (2013).
Reyes-Turcu, F. E., Zhang, K., Zofall, M., Chen, E. & Grewal, S. I. Defects in RNA quality control factors reveal RNAi-independent nucleation of heterochromatin. Nat. Struct. Mol. Biol. 18, 1132–1138 (2011).
Wittmann, S. et al. The conserved protein Seb1 drives transcription termination by binding RNA polymerase II and nascent RNA. Nat. Commun. 8, 14861 (2017).
Lemay, J. F. et al. The Nrd1-like protein Seb1 coordinates cotranscriptional 3′ end processing and polyadenylation site selection. Genes Dev. 30, 1558–1572 (2016).
Sugiyama, T. et al. SHREC, an effector complex for heterochromatic transcriptional silencing. Cell 128, 491–504 (2007).
Marina, D. B., Shankar, S., Natarajan, P., Finn, K. J. & Madhani, H. D. A conserved ncRNA-binding protein recruits silencing factors to heterochromatin through an RNAi-independent mechanism. Genes Dev. 27, 1851–1856 (2013). This article shows that the conserved RNA-binding protein Seb1, an orthologue of S. cerevisiae Nrd1, is an essential mediator of RNAi-independent heterochromatin assembly at fission yeast pericentromeric repeats.
Shirai, A. et al. Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly. eLife 6, e25317 (2017).
Johnson, W. L. et al. RNA-dependent stabilization of SUV39H1 at constitutive heterochromatin. eLife 6, e25299 (2017).
Velazquez Camacho, O. et al. Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation. eLife 6, e25293 (2017). References 75–77 show that the nucleic acid binding activities of the chromodomain of SUV39 enzymes stabilize their association with heterochromatin.
Chu, C. et al. Systematic discovery of Xist RNA binding proteins. Cell 161, 404–416 (2015).
Minajigi, A. et al. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. Science 349, aab2276 (2015).
Monfort, A. et al. Identification of Spen as a crucial factor for Xist function through forward genetic screening in haploid embryonic stem cells. Cell Rep. 12, 554–561 (2015).
Moindrot, B. et al. A Pooled shRNA screen identifies Rbm15, Spen, and Wtap as factors required for Xist RNA-mediated silencing. Cell Rep. 12, 562–572 (2015).
McHugh, C. A. et al. The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature 521, 232–236 (2015). References 80–82 identify the RNA binding protein SPEN (SHARP) as crucial for the establishment of X inactivation in mice.
Mira-Bontenbal, H. & Gribnau, J. New Xist-interacting proteins in X-chromosome inactivation. Curr. Biol. 26, R338–R342 (2016).
Folco, H. D., Pidoux, A. L., Urano, T. & Allshire, R. C. Heterochromatin and RNAi are required to establish CENP-A chromatin at centromeres. Science 319, 94–97 (2008).
Buscaino, A. et al. Distinct roles for Sir2 and RNAi in centromeric heterochromatin nucleation, spreading and maintenance. EMBO J. 32, 1250–1264 (2013).
Ekwall, K., Olsson, T., Turner, B. M., Cranston, G. & Allshire, R. C. Transient inhibition of histone deacetylation alters the structural and functional imprint at fission yeast centromeres. Cell 91, 1021–1032 (1997).
Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002).
Djupedal, I. et al. Analysis of small RNA in fission yeast; centromeric siRNAs are potentially generated through a structured RNA. EMBO J. 28, 3832–3844 (2009).
Halic, M. & Moazed, D. Dicer-independent primal RNAs trigger RNAi and heterochromatin formation. Cell 140, 504–516 (2010).
Simmer, F. et al. Hairpin RNA induces secondary small interfering RNA synthesis and silencing in trans in fission yeast. EMBO Rep. 11, 112–118 (2010).
Iida, T., Nakayama, J. & Moazed, D. siRNA-mediated heterochromatin establishment requires HP1 and is associated with antisense transcription. Mol. Cell 31, 178–189 (2008).
Sadeghi, L., Prasad, P., Ekwall, K., Cohen, A. & Svensson, J. P. The Paf1 complex factors Leo1 and Paf1 promote local histone turnover to modulate chromatin states in fission yeast. EMBO Rep. 16, 1673–1687 (2015).
Kowalik, K. M. et al. The Paf1 complex represses small-RNA-mediated epigenetic gene silencing. Nature 520, 248–252 (2015).
Verrier, L. et al. Global regulation of heterochromatin spreading by Leo1. Open Biol. 5, 150045 (2015). References 92–94 show that the Paf1 complex, which is a Pol II elongation factor, inhibits heterochromatin assembly.
Yu, R., Jih, G., Iglesias, N. & Moazed, D. Determinants of heterochromatic siRNA biogenesis and function. Mol. Cell 53, 262–276 (2014).
Wang, J. et al. The proper connection between shelterin components is required for telomeric heterochromatin assembly. Genes Dev. 30, 827–839 (2016).
Kanoh, J., Sadaie, M., Urano, T. & Ishikawa, F. Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr. Biol. 15, 1808–1819 (2005).
Hansen, K. R., Ibarra, P. T. & Thon, G. Evolutionary-conserved telomere-linked helicase genes of fission yeast are repressed by silencing factors, RNAi components and the telomere-binding protein Taz1. Nucleic Acids Res. 34, 78–88 (2006).
Weick, E. M. & Miska, E. A. piRNAs: from biogenesis to function. Development 141, 3458–3471 (2014).
Das, P. P. et al. Piwi and piRNAs act upstream of an endogenous siRNA pathway to suppress Tc3 transposon mobility in the Caenorhabditis elegans germline. Mol. Cell 31, 79–90 (2008).
Gu, T. & Elgin, S. C. Maternal depletion of Piwi, a component of the RNAi system, impacts heterochromatin formation in Drosophila. PLoS Genet. 9, e1003780 (2013).
Blevins, T. et al. A two-step process for epigenetic inheritance in Arabidopsis. Mol. Cell 54, 30–42 (2014).
Wutz, A. & Jaenisch, R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol. Cell 5, 695–705 (2000).
Csankovszki, G., Nagy, A. & Jaenisch, R. Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J. Cell Biol. 153, 773–784 (2001).
Elgin, S. C. & Reuter, G. Position-effect variegation, heterochromatin formation, and gene silencing in Drosophila. Cold Spring Harb. Perspect. Biol. 5, a017780 (2013).
Spofford, J. B. Parental control of position-effect variegation: I. Parental heterochromatin and expression of the white locus in compound-X Drosophila melanogaster. Proc. Natl Acad. Sci. USA 45, 1003–1007 (1959).
Tartof, K. D., Hobbs, C. & Jones, M. A structural basis for variegating position effects. Cell 37, 869–878 (1984).
Talbert, P. B. & Henikoff, S. A reexamination of spreading of position-effect variegation in the white-roughest region of Drosophila melanogaster. Genetics 154, 259–272 (2000).
Hecht, A., Strahl-Bolsinger, S. & Grunstein, M. Spreading of transcriptional repressor SIR3 from telomeric heterochromatin. Nature 383, 92–96 (1996).
Hecht, A., Laroche, T., Strahl-Bolsinger, S., Gasser, S. M. & Grunstein, M. Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell 80, 583–592 (1995).
Renauld, H. et al. Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by SIR3 dosage. Genes Dev. 7, 1133–1145 (1993).
Al-Sady, B., Madhani, H. D. & Narlikar, G. J. Division of labor between the chromodomains of HP1 and Suv39 methylase enables coordination of heterochromatin spread. Mol. Cell 51, 80–91 (2013).
Yamada, T., Fischle, W., Sugiyama, T., Allis, C. D. & Grewal, S. I. The nucleation and maintenance of heterochromatin by a histone deacetylase in fission yeast. Mol. Cell 20, 173–185 (2005).
Obersriebnig, M. J., Pallesen, E. M., Sneppen, K., Trusina, A. & Thon, G. Nucleation and spreading of a heterochromatic domain in fission yeast. Nat. Commun. 7, 11518 (2016).
Erdel, F. & Greene, E. C. Generalized nucleation and looping model for epigenetic memory of histone modifications. Proc. Natl Acad. Sci. USA 113, E4180–E4189 (2016).
Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017). The paper demonstrates that human HP1 α can undergo phase separation in vitro upon phosphorylation and that this correlates with its ability to form foci in vivo.
Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017). The article shows that D. melanogaster HP1a can undergo phase separation in vitro and that heterochromatic foci in fly and human cells have the properties of liquid droplets.
Simon, M. D. et al. High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504, 465–469 (2013). High-resolution RNA mapping identifies the phases of XIST assembly during X inactivation, revealing initial binding to gene-rich regions before appearance in gene-poor regions.
Engreitz, J. M. et al. The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341, 1237973 (2013). The article examines X inactivation in the context of long-range chromatin interactions and concludes that XIST first spreads from the X chromosome inactivation centre to regions in close 3D proximity to the initiating locus.
White, W. M., Willard, H. F., Van Dyke, D. L. & Wolff, D. J. The spreading of X inactivation into autosomal material of an x;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA. Am. J. Hum. Genet. 63, 20–28 (1998).
Popova, B. C., Tada, T., Takagi, N., Brockdorff, N. & Nesterova, T. B. Attenuated spread of X-inactivation in an X;autosome translocation. Proc. Natl Acad. Sci. USA 103, 7706–7711 (2006).
Bala Tannan, N. et al. DNA methylation profiling in X;autosome translocations supports a role for L1 repeats in the spread of X chromosome inactivation. Hum. Mol. Genet. 23, 1224–1236 (2014).
Wutz, A., Rasmussen, T. P. & Jaenisch, R. Chromosomal silencing & localization are mediated by different domains of Xist RNA. Nat. Genet. 30, 167–174 (2002).
Lee, J. T. & Jaenisch, R. Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386, 275–279 (1997).
Herzing, L. B., Romer, J. T., Horn, J. M. & Ashworth, A. Xist has properties of the X-chromosome inactivation centre. Nature 386, 272–275 (1997).
da Rocha, S. T. & Heard, E. Novel players in X inactivation: insights into Xist-mediated gene silencing and chromosome conformation. Nat. Struct. Mol. Biol. 24, 197–204 (2017).
Jiang, J. et al. Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013).
Raab, J. R. et al. Human tRNA genes function as chromatin insulators. EMBO J. 31, 330–350 (2012).
Donze, D., Adams, C. R., Rine, J. & Kamakaka, R. T. The boundaries of the silenced HMR domain in Saccharomyces cerevisiae. Genes Dev. 13, 698–708 (1999).
Scott, K. C., Merrett, S. L. & Willard, H. F. A heterochromatin barrier partitions the fission yeast centromere into discrete chromatin domains. Curr. Biol. 16, 119–129 (2006).
Noma, K., Cam, H. P., Maraia, R. J. & Grewal, S. I. A role for TFIIIC transcription factor complex in genome organization. Cell 125, 859–872 (2006).
Coveney, J. & Woodland, H. R. The DNase I sensitivity of Xenopus laevis genes transcribed by RNA polymerase III. Nature 298, 578–580 (1982).
DeLotto, R. & Schedl, P. Internal promoter elements of transfer RNA genes are preferentially exposed in chromatin. J. Mol. Biol. 179, 607–628 (1984).
Takahashi, K. et al. A low copy number central sequence with strict symmetry and unusual chromatin structure in fission yeast centromere. Mol. Biol. Cell 3, 819–835 (1992).
Aygun, O., Mehta, S. & Grewal, S. I. HDAC-mediated suppression of histone turnover promotes epigenetic stability of heterochromatin. Nat. Struct. Mol. Biol. 20, 547–554 (2013).
Hartley, P. D. & Madhani, H. D. Mechanisms that specify promoter nucleosome location and identity. Cell 137, 445–458 (2009).
Raisner, R. M. et al. Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin. Cell 123, 233–248 (2005).
Meneghini, M. D., Wu, M. & Madhani, H. D. Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell 112, 725–736 (2003).
Venkatasubrahmanyam, S., Hwang, W. W., Meneghini, M. D., Tong, A. H. & Madhani, H. D. Genome-wide, as opposed to local, antisilencing is mediated redundantly by the euchromatic factors Set1 and H2A.Z. Proc. Natl Acad. Sci. USA 104, 16609–16614 (2007).
Tompa, R. & Madhani, H. D. Histone H3 lysine 36 methylation antagonizes silencing in Saccharomyces cerevisiae independently of the Rpd3S histone deacetylase complex. Genetics 175, 585–593 (2007).
Santos-Rosa, H., Bannister, A. J., Dehe, P. M., Geli, V. & Kouzarides, T. Methylation of H3 lysine 4 at euchromatin promotes Sir3p association with heterochromatin. J. Biol. Chem. 279, 47506–47512 (2004).
van Leeuwen, F., Gafken, P. R. & Gottschling, D. E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).
Verzijlbergen, K. F., Faber, A. W., Stulemeijer, I. J. & van Leeuwen, F. Multiple histone modifications in euchromatin promote heterochromatin formation by redundant mechanisms in Saccharomyces cerevisiae. BMC Mol. Biol. 10, 76 (2009).
Li, X. et al. Chromatin boundaries require functional collaboration between the hSET1 and NURF complexes. Blood 118, 1386–1394 (2011).
Ayoub, N. et al. A novel jmjC domain protein modulates heterochromatization in fission yeast. Mol. Cell. Biol. 23, 4356–4370 (2003).
Trewick, S. C., McLaughlin, P. J. & Allshire, R. C. Methylation: lost in hydroxylation? EMBO Rep. 6, 315–320 (2005).
Zofall, M. & Grewal, S. I. Swi6/HP1 recruits a JmjC domain protein to facilitate transcription of heterochromatic repeats. Mol. Cell 22, 681–692 (2006).
Trewick, S. C., Minc, E., Antonelli, R., Urano, T. & Allshire, R. C. The JmjC domain protein Epe1 prevents unregulated assembly and disassembly of heterochromatin. EMBO J. 26, 4670–4682 (2007).
Braun, S. et al. The Cul4-DdbCdt2 ubiquitin ligase inhibits invasion of a boundary-associated antisilencing factor into heterochromatin. Cell 144, 41–54 (2011).
Garcia, J. F., Al-Sady, B. & Madhani, H. D. Intrinsic toxicity of unchecked heterochromatin spread is suppressed by redundant chromatin boundary functions in Schizosacchromyces pombe. G3 5, 1453–1461 (2015).
Wang, J., Reddy, B. D. & Jia, S. Rapid epigenetic adaptation to uncontrolled heterochromatin spreading. eLife 4, e06179 (2015). Increased H3K9me-dependent heterochromatin formation in fission yeast cells lacking factors that counteract its assembly can be suppressed by spontaneous heterochromatin-mediated silencing of genes encoding components of the Clr4 histone H3K9 methyltransferase complex.
Lee, N. N. et al. Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance. Cell 155, 1061–1074 (2013).
Zofall, M. et al. RNA elimination machinery targeting meiotic mRNAs promotes facultative heterochromatin formation. Science 335, 96–100 (2012).
Yamanaka, S. et al. RNAi triggered by specialized machinery silences developmental genes and retrotransposons. Nature 493, 557–560 (2013).
Joh, R. I. et al. Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by Argonaute-associated small RNAs. Mol. Cell 64, 1088–1101 (2016). References 152–155 report the presence of regulated heterochromatin islands outside of the main heterochromatin domains at centromeres, telomeres and the mating-type loci in fission yeast.
Dumesic, P. A. et al. Product binding enforces the genomic specificity of a yeast polycomb repressive complex. Cell 160, 204–218 (2015). Reports the first yeast Polycomb system in C. neoformans and reveals that tethering of its PRC2-like complex to sites of previous action at subtelomeric regions prevents it from erroneously modifying H3K9me-marked centromeric heterochromatin.
Alabert, C. & Groth, A. Chromatin replication and epigenome maintenance. Nat. Rev. Mol. Cell. Biol. 13, 153–167 (2012).
Jones, P. A. & Liang, G. Rethinking how DNA methylation patterns are maintained. Nat. Rev. Genet. 10, 805–811 (2009).
Freitag, M., Hickey, P. C., Khlafallah, T. K., Read, N. D. & Selker, E. U. HP1 is essential for DNA methylation in Neurospora. Mol. Cell 13, 427–434 (2004).
Du, J., Johnson, L. M., Jacobsen, S. E. & Patel, D. J. DNA methylation pathways and their crosstalk with histone methylation. Nat. Rev. Mol. Cell. Biol. 16, 519–532 (2015).
Wang, X. & Moazed, D. DNA sequence-dependent epigenetic inheritance of gene silencing and histone H3K9 methylation. Science 356, 88–91 (2017).
Kagansky, A. et al. Synthetic heterochromatin bypasses RNAi and centromeric repeats to establish functional centromeres. Science 324, 1716–1719 (2009).
Audergon, P. N. et al. Epigenetics. Restricted epigenetic inheritance of H3K9 methylation. Science 348, 132–135 (2015).
Ragunathan, K., Jih, G. & Moazed, D. Epigenetic inheritance uncoupled from sequence-specific recruitment. Science 348, 1258699 (2015). References 163 and 164 demonstrate that transient tethering of the Clr4 H3K9 methyltransferase to a genomic site in fission yeast results in the formation of heritable heterochromatin and gene silencing, provided that a histone demethylase, Epe1, is removed from cells.
Bintu, L. et al. Dynamics of epigenetic regulation at the single-cell level. Science 351, 720–724 (2016).
Amabile, A. et al. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 167, 219–232.e14 (2016).
Hathaway, N. A. et al. Dynamics and memory of heterochromatin in living cells. Cell 149, 1447–1460 (2012).
Berry, S., Hartley, M., Olsson, T. S., Dean, C. & Howard, M. Local chromatin environment of a Polycomb target gene instructs its own epigenetic inheritance. eLife 4, e07205 (2015).
Laprell, F., Finkl, K. & Muller, J. Propagation of Polycomb-repressed chromatin requires sequence-specific recruitment to DNA. Science 356, 85–88 (2017).
Coleman, R. T. & Struhl, G. Causal role for inheritance of H3K27me3 in maintaining the OFF state of a Drosophila HOX gene. Science http://dx.doi.org/10.1126/science.aai8236 (2017). References 169 and 170 show that binding sites for DNA-binding proteins are required for the heritability of H3K27me-marked silent domains in D. melanogaster.
Grewal, S. I. & Klar, A. J. Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86, 95–101 (1996).
Jia, S., Noma, K. & Grewal, S. I. RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins. Science 304, 1971–1976 (2004).
Taneja, N. et al. SNF2 family protein Fft3 suppresses nucleosome turnover to promote epigenetic inheritance and proper replication. Mol. Cell 66, 50–62.e6 (2017).
Steglich, B. et al. The Fun30 chromatin remodeler Fft3 controls nuclear organization and chromatin structure of insulators and subtelomeres in fission yeast. PLoS Genet. 11, e1005101 (2015).
Stralfors, A., Walfridsson, J., Bhuiyan, H. & Ekwall, K. The FUN30 chromatin remodeler, Fft3, protects centromeric and subtelomeric domains from euchromatin formation. PLOS Genet. 7, e1001334 (2011).
Mari-Ordonez, A. et al. Reconstructing de novo silencing of an active plant retrotransposon. Nat. Genet. 45, 1029–1039 (2013).
Lanciano, S. et al. Sequencing the extrachromosomal circular mobilome reveals retrotransposon activity in plants. PLOS Genet. 13, e1006630 (2017).
Hickey, D. A. Selfish DNA: a sexually-transmitted nuclear parasite. Genetics 101, 519–531 (1982).
Zeller, P. et al. Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability. Nat. Genet. 48, 1385–1395 (2016). This article reveals that C. elegans mutants lacking H3K9 methylation have increased levels of R-loops and consequent genetic instability.
Klattenhoff, C. et al. The Drosophila HP1 homolog Rhino is required for transposon silencing and piRNA production by dual-strand clusters. Cell 138, 1137–1149 (2009).
Sienski, G., Donertas, D. & Brennecke, J. Transcriptional silencing of transposons by Piwi and maelstrom and its impact on chromatin state and gene expression. Cell 151, 964–980 (2012).
Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).
Aravin, A. A. et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell 31, 785–799 (2008).
Kojima-Kita, K. et al. MIWI2 as an effector of DNA methylation and gene silencing in embryonic male germ cells. Cell Rep. 16, 2819–2828 (2016).
Kuramochi-Miyagawa, S. et al. DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev. 22, 908–917 (2008).
Peng, J. C. & Karpen, G. H. H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat. Cell Biol. 9, 25–35 (2007).
Chiolo, I. et al. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144, 732–744 (2011).
Jakob, B. et al. DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin. Nucleic Acids Res. 39, 6489–6499 (2011).
Ryu, T. et al. Heterochromatic breaks move to the nuclear periphery to continue recombinational repair. Nat. Cell Biol. 17, 1401–1411 (2015).
Tsouroula, K. et al. Temporal and spatial uncoupling of DNA double strand break repair pathways within mammalian heterochromatin. Mol. Cell 63, 293–305 (2016).
Janssen, A. et al. A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin. Genes Dev. 30, 1645–1657 (2016).
McKinley, K. L. & Cheeseman, I. M. The molecular basis for centromere identity and function. Nat. Rev. Mol. Cell. Biol. 17, 16–29 (2016).
Sullivan, L. L., Maloney, K. A., Towers, A. J., Gregory, S. G. & Sullivan, B. A. Human centromere repositioning within euchromatin after partial chromosome deletion. Chromosome Res. 24, 451–466 (2016).
Sato, H., Masuda, F., Takayama, Y., Takahashi, K. & Saitoh, S. Epigenetic inactivation and subsequent heterochromatinization of a centromere stabilize dicentric chromosomes. Curr. Biol. 22, 658–667 (2012).
Nakano, M. et al. Inactivation of a human kinetochore by specific targeting of chromatin modifiers. Dev. Cell 14, 507–522 (2008).
Cardinale, S. et al. Hierarchical inactivation of a synthetic human kinetochore by a chromatin modifier. Mol. Biol. Cell 20, 4194–4204 (2009).
Uhlmann, F. SMC complexes: from DNA to chromosomes. Nat. Rev. Mol. Cell. Biol. 17, 399–412 (2016).
Bernard, P. et al. Requirement of heterochromatin for cohesion at centromeres. Science 294, 2539–2542 (2001).
Nonaka, N. et al. Recruitment of cohesin to heterochromatic regions by Swi6/HP1 in fission yeast. Nat. Cell Biol. 4, 89–93 (2002).
Pidoux, A. L., Uzawa, S., Perry, P. E., Cande, W. Z. & Allshire, R. C. Live analysis of lagging chromosomes during anaphase and their effect on spindle elongation rate in fission yeast. J. Cell Sci. 113, 4177–4191 (2000).
Gregan, J. et al. The kinetochore proteins Pcs1 and Mde4 and heterochromatin are required to prevent merotelic orientation. Curr. Biol. 17, 1190–1200 (2007).
Ekwall, K. et al. The chromodomain protein Swi6: a key component at fission yeast centromeres. Science 269, 1429–1431 (1995).
Tanno, Y. et al. The inner centromere-shugoshin network prevents chromosomal instability. Science 349, 1237–1240 (2015).
Klar, A. J., Ishikawa, K. & Moore, S. A. Unique DNA recombination mechanism of the mating/cell-type switching of fission yeasts: a review. Microbiol. Spectr. 2, http://dx.doi.org/10.1128/microbiolspec.MDNA3-0003-2014 (2014).
Jia, S., Yamada, T. & Grewal, S. I. Heterochromatin regulates cell type-specific long-range chromatin interactions essential for directed recombination. Cell 119, 469–480 (2004).
Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell 151, 994–1004 (2012). This paper shows that megabase-sized heterochromatin domains in somatic cells impede the binding of pluripotency transcription factors to their targets.
Becker, J. S., Nicetto, D. & Zaret, K. S. H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet. 32, 29–41 (2016).
Chen, J. et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat. Genet. 45, 34–42 (2013).
Sridharan, R. et al. Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1γ in reprogramming to pluripotency. Nat. Cell Biol. 15, 872–882 (2013).
Cheloufi, S. et al. The histone chaperone CAF-1 safeguards somatic cell identity. Nature 528, 218–224 (2015).
Matoba, S. et al. Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation. Cell 159, 884–895 (2014).
Castro-Diaz, N. et al. Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev. 28, 1397–1409 (2014).
Jacobs, F. M. J. et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245 (2014).
Wolf, D. & Goff, S. P. Embryonic stem cells use ZFP809 to silence retroviral DNAs. Nature 458, 1201–1204 (2009).
Imbeault, M., Helleboid, P.-Y. & Trono, D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550–554 (2017). This paper shows that transposable elements in tetrapods are recognized and silenced by KRAB-ZFP proteins that coevolve with the elements in an ongoing arms race.
Timms, R. T., Tchasovnikarova, I. A. & Lehner, P. J. Position-effect variegation revisited: HUSHing up heterochromatin in human cells. Bioessays 38, 333–343 (2016).
Tchasovnikarova, I. A. et al. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348, 1481–1485 (2015). A genetic screen in haploid cells for factors that silence an integrated retroviral reporter identifies a protein complex containing the H3K9 methyltransferase SETDB1 and the H32K9me-binding MPP8 chromodomain protein.
Wolf, G. et al. The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses. Genes Dev. 29, 538–554 (2015).
Dalgaard, K. et al. Trim28 haploinsufficiency triggers bi-stable epigenetic obesity. Cell 164, 353–364 (2016). Haploinsufficiency of a component of the KRAB–KAP1 H3K9me-recruiting complex is shown to result in epigenetic variability in obesity in mice.
Zhang, W. et al. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348, 1160–1163 (2015).
Janke, R., Dodson, A. E. & Rine, J. Metabolism and epigenetics. Annu. Rev. Cell Dev. Biol. 31, 473–496 (2015).
Sharma, U. & Rando, O. J. Metabolic inputs into the epigenome. Cell Metab. 25, 544–558 (2017).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).
Carey, B. W., Finley, L. W. S., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).
Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016). References 223–226 show how imbalances in metabolite levels generated by the tricarboxylic acid cycle because of mutation, oversupply or undersupply of nutrients result in altered cell fate and tumorigenesis.
Janke, R., Iavarone, A. T. & Rine, J. Oncometabolite D-2-hydroxyglutarate enhances gene silencing through inhibition of specific H3K36 histone demethylases. eLife 6, e22451 (2017).
Passarge, E. Emil Heitz and the concept of heterochromatin: longitudinal chromosome differentiation was recognized fifty years ago. Am. J. Hum. Genet. 31, 106 (1979).
Muller, H. J. Types of visible variations induced by X-rays in Drosophila. J. Genet. 22, 299–334 (1930).
Schultz, J. Variegation in Drosophila and the inert chromosome regions. Proc. Natl Acad. Sci. USA 22, 27–33 (1936).
Gowen, J. & Gay, E. Chromosome constitution and behavior in eversporting and mottling in Drosophila melanogaster. Genetics 19, 189 (1934).
Dimitri, P. & Pisano, C. Position effect variegation in Drosophila melanogaster: relationship between suppression effect and the amount of Y chromosome. Genetics 122, 793–800 (1989).
Spradling, A. C. & Karpen, G. H. Sixty years of mystery. Genetics 126, 779–784 (1990).
Henikoff, S. Position-effect variegation after 60 years. Trends Genet. 6, 422–426 (1990).
Reute, G. & Spierer, P. Position effect variegation and chromatin proteins. BioEssays 14, 605–612 (1992).
Britten, R. J. & Kohne, D. E. Repeated Sequences in DNA. Science 161, 529–540 (1968).
Kit, S. Equilibrium sedimentation in density gradients of DNA preparations from animal tissues. J. Mol. Biol. 3, 711–716 (1961).
Yasmineh, W. G. & Yunis, J. J. Localization of mouse satellite DNA in constitutive heterochromatin. Exp. Cell Res. 59, 69–75 (1970).
Flamm, W. G., Bond, H. E., Burr, H. E. & Bond, S. B. Satellite DNA isolated from mouse liver; some physical and metabolic properties. Biochim. Biophys. Acta 123, 652–654 (1966).
Flamm, W. G., McCallum, M. & Walker, P. M. The isolation of complementary strands from a mouse DNA fraction. Proc. Natl Acad. Sci. USA 57, 1729–1734 (1967).
Filipski, J., Thiery, J.-P. & Bernardi, G. An analysis of the bovine genome by Cs2SO4—Ag+ density gradient centrifugation. J. Mol. Biol. 80, 177–197 (1973).
Southern, E. M. Base sequence and evolution of guinea-pig α-satellite DNA. Nature 227, 794–798 (1970).
Fry, K. et al. Nucleotide sequence of HS-β satellite DNA from kangaroo rat Dipodomys ordii. Proc. Natl Acad. Sci. USA 70, 2642 (1973).
Jones, K. W. Chromosomal and nuclear location of mouse satellite DNA in individual cells. Nature 225, 912–915 (1970).
Pardue, M. L. & Gall, J. G. Chromosomal localization of mouse satellite DNA. Science 168, 1356–1358 (1970).
Rae, P. M. M. & Franke, W. W. The interphase distribution of satellite DNA-containing heterochromatin in mouse nuclei. Chromosoma 39, 443–456 (1972).
Flamm, W. G., Walker, P. M. & McCallum, M. Some properties of the single strands isolated from the DNA of the nuclear satellite of the mouse (Mus musculus). J. Mol. Biol. 40, 423–443 (1969).
Yunis, J. J. & Yasmineh, W. G. Satellite DNA in constitutive heterochromatin of the guinea pig. Science 168, 263–265 (1970).
Lima-de-Faria, A. & Jaworska, H. Late DNA Synthesis in heterochromatin. Nature 217, 138–142 (1968).
Gall, J., Cohen, E. & Polan, M. Repetitive DNA sequences in Drosophila. Chromosoma 33, 319–344 (1971).
Deans, C. & Maggert, K. A. What do you mean, “epigenetic”? Genetics 199, 887–896 (2015).
Bird, A. Perceptions of epigenetics. Nature 447, 396–398 (2007).
Castel, S. E. & Martienssen, R. A. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Mol. Cell. Biol. 14, 100–112 (2013).
Acknowledgements
R.C.A. is a Wellcome Principal Research Fellow; his research is supported by the UK Wellcome Trust (200885) and core funding of the UK Wellcome Centre for Cell Biology (203149). Research in the laboratory of H.D.M. is supported by grants from the US National Institutes of Health. H.D.M. is a Chan-Zuckerberg BioHub investigator. The authors apologize to colleagues whose work could not be cited because of length restrictions. The authors dedicate this piece to the memory of A. Klar, whose pioneering studies of cell-type specification and gene silencing in Saccharomyces cerevisiae and Schizosaccharomyces pombe paved the way for many advances.
Author information
Authors and Affiliations
Contributions
R.C.A. and H.D.M. each researched data for the article, made substantial contributions to the discussion of content, wrote the manuscript and reviewed and edited it before submission.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Post-translational modifications
-
(PTMs). Chemical groups (such as methyl or acetyl) on amino acid side chains that are enzymatically added by 'writer', removed by 'eraser' and recognized by 'reader' protein modules.
- Satellite repeats
-
Short repetitive sequences that exhibit a distinct satellite peak on buoyant density gradients owing to their skewed base composition.
- Constitutive heterochromatin
-
In most eukaryotes, heterochromatin that is consistently formed throughout the cell cycle and in many cell types, for example, centrome-reassociated heterochromatin.
- Facultative heterochromatin
-
Locus-specific and cell-type-specific heterochromatin, for example, the inactive X chromosome in mammals.
- Chromoshadow domain
-
(CSD). Dimerization domain in heterochromatin protein 1-related proteins that forms a peptide-binding groove at the dimer interface that can recruit additional heterochromatin proteins.
- Argonaute
-
Proteins with PAZ and Piwi domains that are loaded with small RNAs, which target them and their associated proteins to long RNAs that bear homology to the small RNA.
- Pericentromeric heterochromatin
-
Large blocks of heterochromatin formed on the tandem repeats that surround the centromere–kinetochore region.
- X chromosome inactivation
-
Mechanism of dosage compensation in female mammals in which one of the two X chromosomes is inactivated by the formation of facultative heterochromatin.
- X-inactive specific transcript
-
(XIST). Long noncoding RNA that designates the X chromosome from which it is expressed for X chromosome inactivation.
- Piwi-associated RNAs
-
(piRNAs). Small RNAs associated with Piwi members of the Argonaute protein superfamily, which promotes repression of transposable elements in animal gonads.
- R-loops
-
Nascent RNA that remains associated with its DNA template through hybridization, thereby dislodging the opposite, nontemplate DNA strand.
- Heterochromatin islands
-
Extensive domains of heterochromatin on chromosome arms, which are distinct from the main centromeric and telomeric heterochromatin domains.
- Reprogramming-resistant regions
-
Large lineage-specific chromosomal regions that are assembled into heterochromatin and thus resist binding by reprogramming factors.
- Endogenous retroelements
-
Mobile elements that replicate through reverse transcription followed by genomic integration. The term also includes degenerate, immobile elements.
Rights and permissions
About this article
Cite this article
Allshire, R., Madhani, H. Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol 19, 229–244 (2018). https://doi.org/10.1038/nrm.2017.119
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm.2017.119
This article is cited by
-
Structural insights into the binding mechanism of Clr4 methyltransferase to H3K9 methylated nucleosome
Scientific Reports (2024)
-
Interrogating epigenetic mechanisms with chemically customized chromatin
Nature Reviews Genetics (2024)
-
DNMT3B PWWP mutations cause hypermethylation of heterochromatin
EMBO Reports (2024)
-
Epigenomic insights into common human disease pathology
Cellular and Molecular Life Sciences (2024)
-
Chromatin organization and behavior in HRAS-transformed mouse fibroblasts
Chromosoma (2024)
