The regional sequestration of heterochromatin structural proteins is critical to form and maintain silent chromatin

(2022) 15:5 Oh et al. Epigenetics & Chromatin https://doi.org/10.1186/s13072-022-00435-w Epigenetics & Chromatin Open Access REVIEW The regional sequestration of heterochromatin structural proteins is critical to form and maintain silent chromatin Junsoo Oh†, Soojin Yeom†, Jiyeon Park and Jung‑Shin Lee* Abstract: Budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe are good models for heterochromatin study. In S. pombe, H3K9 methylation and Swi6, an ortholog of mammalian HP1, lead to heterochromatin formation. However, S. cerevisiae does not have known epigenetic silencing markers and instead has Sir proteins to regulate silent chromatin formation. Although S. cerevisiae and S. pombe form and maintain heterochromatin via mechanisms that appear to be fundamentally different, they share important common features in the heterochromatin structural proteins. Heterochromatin loci are localized at the nuclear periphery by binding to perinuclear membrane proteins, thereby producing distinct heterochromatin foci, which sequester heterochromatin structural proteins. In this review, we discuss the nuclear peripheral anchoring of heterochromatin foci and its functional relevance to heterochromatin formation and maintenance. Keywords: Saccharomyces cerevisiae, Schizosaccharomyces pombe, Heterochromatin structural proteins, SIR complex, Swi6 *Correspondence: † Junsoo Oh and Soojin Yeom are co-first authors Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, 1 Kangwondeahak‑gil, Chuncheon 24341, Republic of Korea © The Author(s) 2022. 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Epigenetics & Chromatin (2022) 15:5 Page 2 of 13 Graphical Abstract S. cerevisiae and S. pombe INMPs Nups INMPs Silent chroman Nucleus Euchroman Heterochroman structural proteins in the nuclear subcompartments at nuclear periphery 1) 2) 3) 4) 5) are ghtly bound to nucleosomes are oligomerized induce conformaonal changes of bound nucleosomes are altered in their conformaons by binding with nucleosomes form disnct physicochemical environments disnguished from outer environments (in S. pombe) to form and maintain heterochroman structure : Heterochroman structural proteins (Sir2/3/4, Rap1 in S.cerevisiae and Swi6 in S.pombe) : RNA polymerase II : Disnct nuclear subcompartments of heterochroman structural proteins and heterochroman loci Introduction Many DNA-templated processes, such as replication, transcription, and DNA repair, are regulated in the context of chromatin structure, which is classified into euchromatin and heterochromatin. Euchromatin is less condensed and more easily accessed by RNA polymerase II and transcription factors, which enables active transcription. In contrast, heterochromatin maintains highly condensed chromatin regions throughout the cell cycle, impeding the access of various transcription factors and causing gene silencing [1, 2]. In higher eukaryotes, heterochromatin regions are characterized by specific histone modifications, namely the methylation of histone H3K9 and histone H3K27 [1, 3]. H3K9-methylated chromatins are bound by heterochromatin protein 1 (HP1), and this process leads to heterochromatin formation [1, 2, 4, 5]. Saccharomyces cerevisiae and Schizosaccharomyces pombe are well-studied model systems for the investigation of heterochromatin. However, between the two model species, there are many differences in the mechanism of heterochromatin formation and gene silencing. Notably, although the methylation of histone H3K9 and HP1 are well-conserved in S. pombe, neither of this histone modification and heterochromatin factor exist in S. cerevisiae [1, 2, 6]. Instead, in S. cerevisiae, the formation and maintenance of heterochromatins are regulated by the silent information regulator (SIR) complex-silencing system [2, 6, 7]. Although the mechanisms for silent chromatin formation are different in both model systems, they share several essential common features. Heterochromatin regions and heterochromatin structural proteins, the Sir2/3/4 complex in S. cerevisiae and Swi6 in S. pombe, are sequestered in several foci at the nuclear periphery [7–11]. After a brief introduction on the mechanism of heterochromatin formation, we will introduce the regional sequestration of both heterochromatin structural proteins and heterochromatin loci at the nuclear periphery [7–11]. We will further discuss how the sequestered nuclear subcompartments contribute to heterochromatin structure and gene silencing. In sequestered nuclear subcompartments, heterochromatin structural proteins and heterochromatin loci form and maintain heterochromatin structure by the following strategies: (1) heterochromatin structural proteins are oligomerized [7, 12–14]; (2) physical interaction between heterochromatin structural proteins and nucleosomes induces conformational changes of each other [7, 12–14]; (3) although not identified in S. cerevisiae, H3K9-methylated nucleosomes and Swi6 in S. pombe form phase-separated liquid condensates, which maintain distinct biochemical conditions distinguished from the outer environments [7]. Through these strategies, heterochromatin structural proteins are tightly bound to nucleosomes [13, 15]. In addition, neighboring nucleosomes are tightly linked, which enables more compacted chromatin structures and gene silencing [7, 15, 16]. Through this review, we propose the importance of regional sequestration of heterochromatin structural proteins for the formation and maintenance of Oh et al. Epigenetics & Chromatin (2022) 15:5 Page 3 of 13 A HML Sir2 Sir4 Sir4 Sir1 Sir3 Sir3 Sir2 Sir4 Sir4 Sir2 Sir3 Sir2 Sir3 Orc1 Rap1 Abf1 Abf1 Rap1 Orc1 H4K16 Ac E Sir1 Sir3 Ac HMR MAT Sir4 I HML Silent mang type loci C rDNA repeats ChrXII B Rif1 Sir3 Sir3 Sir3 Sir4 Sir2 Sir4 Sir2 Sir4 Sir2 Sir4 Rap1 Rap1 Rap1 Rap1 Sir3 Sir2 RFB 5S I (...truncated)