Current Genetics

, Volume 65, Issue 2, pp 423–428 | Cite as

Epigenetic fates of gene silencing established by heterochromatin spreading in cell identity and genome stability

  • R. A. Greenstein
  • Bassem Al-SadyEmail author


Heterochromatin spreading, the propagation of repressive chromatin along the chromosome, is a reaction critical to genome stability and defense, as well as maintenance of unique cell fates. Here, we discuss the intrinsic properties of the spreading reaction and circumstances under which its products, formed distal to DNA-encoded nucleation sites, can be epigenetically maintained. Finally, we speculate that the epigenetic properties of heterochromatin evolved together with the need to stabilize cellular identity.


Epigenetic inheritance Histone 3 lysine 9 methylation Heterochromatin spreading Cellular identity Chromatin structure Histone turnover DNA methylation 



We would like to thank Sandra Catania for critical reading of the manuscript. R.A.G. was supported by an ARCS Scholarship and a Hooper Graduate Fellowship. B.A.-S. was supported by a grant from the NIH (DP2 GM 123484) and from the UCSF PBBR program.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Human and animal rights statement

No human subjects or animals were used in this study.


  1. Al-Sady B, Madhani HD, Narlikar GJ (2013) Division of labor between the chromodomains of HP1 and Suv39 methylase enables coordination of heterochromatin spread. Mol cell 51(1):80–91CrossRefGoogle Scholar
  2. Angel A et al (2011) A polycomb-based switch underlying quantitative epigenetic memory. Nature 476(7358):105–108CrossRefGoogle Scholar
  3. Angel A et al (2015) Vernalizing cold is registered digitally at FLC. Proc Natl Acad Sci USA 112(13):4146–4151CrossRefGoogle Scholar
  4. Arita K et al (2008) Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455(7214):818–821CrossRefGoogle Scholar
  5. Aygun O, Mehta S, Grewal SI (2013) HDAC-mediated suppression of histone turnover promotes epigenetic stability of heterochromatin. Nat Struct Mol Biol 20(5):547–554CrossRefGoogle Scholar
  6. Bantignies F, Cavalli G (2011) Polycomb group proteins: repression in 3D. Trends Genet 27(11):454–464CrossRefGoogle Scholar
  7. Bernard P et al (2001) Requirement of heterochromatin for cohesion at centromeres. Science 294(5551):2539–2542CrossRefGoogle Scholar
  8. Bonev B, Cavalli G (2016) Organization and function of the 3D genome. Nat Rev Genet 17(12):772CrossRefGoogle Scholar
  9. Boscheron C et al (1996) Cooperation at a distance between silencers and proto-silencers at the yeast HML locus. EMBO J 15(9):2184–2195CrossRefGoogle Scholar
  10. Chen SY (1948) Action de la température sur trois mutants à panachure de Drosophila melanogaster, w258-18, wm5 et z. Bull Biol Fr Belg 82(2–3):114–129Google Scholar
  11. Coleman RT, Struhl G (2017) Causal role for inheritance of H3K27me3 in maintaining the OFF state of a Drosophila HOX gene. Science 356(6333):eaai8236CrossRefGoogle Scholar
  12. Cooper JP et al (1997) Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature 385(6618):744–747CrossRefGoogle Scholar
  13. D’Urso A, Brickner JH (2017) Epigenetic transcriptional memory. Curr Genet 63(3):435–439CrossRefGoogle Scholar
  14. Dekker J, Heard E (2015) Structural and functional diversity of topologically associating domains. FEBS Lett 589(20 Pt A):2877–2884CrossRefGoogle Scholar
  15. Dodd IB et al (2007) Theoretical analysis of epigenetic cell memory by nucleosome modification. Cell 129(4):813–822CrossRefGoogle Scholar
  16. Erdel F, Greene EC (2016) Generalized nucleation and looping model for epigenetic memory of histone modifications. Proc Natl Acad Sci USA 113(29):E4180–E4189CrossRefGoogle Scholar
  17. Esteve PO et al (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20(22):3089–3103CrossRefGoogle Scholar
  18. Geisler SJ, Paro R (2015) Trithorax and Polycomb group-dependent regulation: a tale of opposing activities. Development 142(17):2876–2887CrossRefGoogle Scholar
  19. Greenstein RA et al (2018) Noncoding RNA-nucleated heterochromatin spreading is intrinsically labile and requires accessory elements for epigenetic stability. Elife 7:e32948CrossRefGoogle Scholar
  20. Grewal SIS, Klar AJS (1996) Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86(1):95–101CrossRefGoogle Scholar
  21. Grewal SI, Klar AJ (1997) A recombinationally repressed region between mat2 and mat3 loci shares homology to centromeric repeats and regulates directionality of mating-type switching in fission yeast. Genetics 146(4):1221–1238Google Scholar
  22. Hammond CM et al (2017) Histone chaperone networks shaping chromatin function. Nat Rev Mol Cell Biol 18(3):141–158CrossRefGoogle Scholar
  23. Hansen KR, Ibarra PT, Thon G (2006) 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(1):78–88CrossRefGoogle Scholar
  24. Kakui Y, Uhlmann F (2018) SMC complexes orchestrate the mitotic chromatin interaction landscape. Curr Genet 64(2):335–339CrossRefGoogle Scholar
  25. Kanoh J et al (2005) Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr Biol 15(20):1808–1819CrossRefGoogle Scholar
  26. Kelly M et al (1988) Four mating-type genes control sexual differentiation in the fission yeast. EMBO J 7(5):1537–1547CrossRefGoogle Scholar
  27. Li F et al (2008) Lid2 is required for coordinating H3K4 and H3K9 methylation of heterochromatin and euchromatin. Cell 135(2):272–283CrossRefGoogle Scholar
  28. Margueron R et al (2009) Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461(7265):762–767CrossRefGoogle Scholar
  29. Mathieu O et al (2007) Transgenerational stability of the Arabidopsis epigenome is coordinated by CG methylation. Cell 130(5):851–862CrossRefGoogle Scholar
  30. Narendra V et al (2015) Transcription. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. Science 347(6225):1017–1021CrossRefGoogle Scholar
  31. Nimmo ER, Cranston G, Allshire RC (1994) Telomere-associated chromosome breakage in fission yeast results in variegated expression of adjacent genes. EMBO J 13(16):3801–3811CrossRefGoogle Scholar
  32. Nimmo ER et al (1998) Defective meiosis in telomere-silencing mutants of Schizosaccharomyces pombe. Nature 392(6678):825–828CrossRefGoogle Scholar
  33. Petryk N et al (2018) MCM2 promotes symmetric inheritance of modified histones during DNA replication. Science 361(6409):1389–1392CrossRefGoogle Scholar
  34. Reinberg D, Vales LD (2018) Chromatin domains rich in inheritance. Science 361(6397):33–34CrossRefGoogle Scholar
  35. Reveron-Gomez N et al (2018) Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication. Mol Cell 72(2):239–249CrossRefGoogle Scholar
  36. Saksouk N, Simboeck E, Dejardin J (2015) Constitutive heterochromatin formation and transcription in mammals. Epigenetics Chromatin 8:3CrossRefGoogle Scholar
  37. Sarraf SA, Stancheva I (2004) Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol Cell 15(4):595–605CrossRefGoogle Scholar
  38. Serra-Cardona A, Zhang Z (2018) Replication-coupled nucleosome assembly in the passage of epigenetic information and cell identity. Trends Biochem Sci 43(2):136–148CrossRefGoogle Scholar
  39. Taneja N et al (2017) SNF2 family Protein Fft3 suppresses nucleosome turnover to promote epigenetic inheritance and proper replication. Mol Cell 66(1):50–62 .e6.CrossRefGoogle Scholar
  40. Tchasovnikarova IA et al (2015) GENE SILENCING. epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348(6242):1481–1485CrossRefGoogle Scholar
  41. Wang X, Moazed D (2017) DNA sequence-dependent epigenetic inheritance of gene silencing and histone H3K9 methylation. Science 356(6333):88–91CrossRefGoogle Scholar
  42. Woolcock KJ et al (2012) RNAi keeps Atf1-bound stress response genes in check at nuclear pores. Genes Dev 26(7):683–692CrossRefGoogle Scholar
  43. Yang H et al (2017) Distinct phases of polycomb silencing to hold epigenetic memory of cold in Arabidopsis. Science 357(6356):1142–1145CrossRefGoogle Scholar
  44. Zukowski A, Johnson AM (2018) The interplay of histone H2B ubiquitination with budding and fission yeast heterochromatin. Curr Genet 64(4):799–806CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Microbiology and Immunology, George Williams Hooper FoundationUniversity of California San FranciscoSan FranciscoUSA
  2. 2.TETRAD Graduate ProgramUniversity of California San FranciscoSan FranciscoUSA

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