Epigenetic Regulation of Chromatin States in<i>Schizosaccharomyces pombe</i>

Allshire, Robin C.; Ekwall, Karl

doi:10.1101/cshperspect.a018770

Cited by 173 publications

(201 citation statements)

References 162 publications

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“…In cells lacking components of the RNAi pathway, heterochromatin is not lost at the mat locus and subtelomeres. At those loci, heterochromatin maintenance is RNAi independent, but RNAi is required to establish heterochromatin (Kanoh et al 2005;Hansen et al 2006;Allshire and Ekwall 2015). At subtelomeres, the Shelterin complex binds telomeres and recruits the CLRC methyltransferase and the SHREC deacetylase complexes to maintain heterochromatin (Kanoh et al 2005;Hansen et al 2006;Sugiyama et al 2007;Motamedi et al 2008;Tadeo et al 2013;Wang et al 2016).…”

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confidence: 99%

“…To amplify small RNAs, RITS recruits the RNA-dependent RNA Polymerase complex (RDRC), which synthesizes doublestranded RNA that is processed by Dicer into siRNAs. In addition, RITS recruits the H3K9 methyltransferase complex CLRC to chromatin, which leads to repressive histone 3 lysine 9 methylation (H3K9me), recruitment of HP1 proteins, and heterochromatin formation (Volpe et al 2002;Verdel et al 2004;Allshire and Ekwall 2015;Holoch and Moazed 2015;Martienssen and Moazed 2015;Zocco et al 2016).…”

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Accumulation of RNA on chromatin disrupts heterochromatic silencing

Brönner¹,

Salvi²,

Zocco³

et al. 2017

Genome Res.

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Long noncoding RNAs (lncRNAs) play a conserved role in regulating gene expression, chromatin dynamics, and cell differentiation. They serve as a platform for RNA interference (RNAi)-mediated heterochromatin formation or DNA methylation in many eukaryotic organisms. We found in Schizosaccharomyces pombe that heterochromatin is lost at transcribed regions in the absence of RNA degradation. We show that heterochromatic RNAs are retained on chromatin, form DNA: RNA hybrids, and need to be degraded by the Ccr4-Not complex or RNAi to maintain heterochromatic silencing. The Ccr4-Not complex is localized to chromatin independently of H3K9me and degrades chromatin-associated transcripts, which is required for transcriptional silencing. Overexpression of heterochromatic RNA, but not euchromatic RNA, leads to chromatin localization and loss of silencing of a distant ade6 reporter in wild-type cells. Our results demonstrate that chromatin-bound RNAs disrupt heterochromatin organization and need to be degraded in a process of heterochromatin formation.

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confidence: 99%

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Accumulation of RNA on chromatin disrupts heterochromatic silencing

Brönner¹,

Salvi²,

Zocco³

et al. 2017

Genome Res.

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“…Heterochromatin domains are marked by dimethylated H3K9 that is deposited by Clr4, the sole histone H3K9 methyltransferase in S. pombe. This repressive histone modification is recognized by HP1 proteins, which serve as a platform to recruit other silencing factors such as SHREC, a repressor complex comprising a Snf2-like nucleosome remodeler and a HDAC subunit similar to the mammalian NuRD complex (Grewal 2010;Allshire and Ekwall 2015). Binding and distribution of these factors within the HP1 platform is subject to a complex regulation.…”

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confidence: 99%

“…In fission yeast, the RNAi machinery also contributes to the establishment and maintenance of heterochromatin (Grewal 2010;Allshire and Ekwall 2015). siRNAs are generated from transcripts of heterochromatic repeats by the endonuclease Dicer (Dcr1), the Argonaute-containing complex RITS (RNA-induced transcriptional silencing), and an RNA-dependent RNA polymerase complex (RDRC).…”

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confidence: 99%

Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2

et al. 2016

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Transcriptionally silent chromatin localizes to the nuclear periphery, which provides a special microenvironment for gene repression. A variety of nuclear membrane proteins interact with repressed chromatin, yet the functional role of these interactions remains poorly understood. Here, we show that, in Schizosaccharomyces pombe, the nuclear membrane protein Lem2 associates with chromatin and mediates silencing and heterochromatin localization. Unexpectedly, we found that these functions can be separated and assigned to different structural domains within Lem2, excluding a simple tethering mechanism. Chromatin association and tethering of centromeres to the periphery are mediated by the N-terminal LEM (LAP2-Emerin-MAN1) domain of Lem2, whereas telomere anchoring and heterochromatin silencing require exclusively its conserved C-terminal MSC (MAN1-Src1 C-terminal) domain. Particularly, silencing by Lem2 is epistatic with the Snf2/HDAC (histone deacetylase) repressor complex SHREC at telomeres, while its necessity can be bypassed by deleting Epe1, a JmjC protein with anti-silencing activity. Furthermore, we found that loss of Lem2 reduces heterochromatin association of SHREC, which is accompanied by increased binding of Epe1. This reveals a critical function of Lem2 in coordinating these antagonistic factors at heterochromatin. The distinct silencing and localization functions mediated by Lem2 suggest that these conserved LEM-containing proteins go beyond simple tethering to play active roles in perinuclear silencing.

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“…Fission yeast centromeric chromatin (Allshire and Ekwall 2015) consists of a central core (cnt) and internal inverted repeats (imr), defined by the presence of CENP-A and methylated histone H3 K4 chromatin, flanked by heterochromatic outer repeats (otr) marked by methylated histone H3 K9 (Partridge et al 2000;Takahashi et al 2000;Kniola et al 2001). The constitutive centromere-associated network (CCAN) forms the inner kinetochore and consists of more than a dozen conserved proteins, including fission yeast Mis6 (CENP-I in mammalian cells) that promotes incorporation of CENP-A at the centromere (McAinsh and Meraldi 2011;Westhorpe and Straight 2015).…”

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Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe

George

Walworth

2015

Genetics

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Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis. Genetic analysis implicates a histone deacetylase (HDAC)-linked pathway in suppression because HDAC mutants clr6-1, clr3D, and sir2D, though not hos2D, also promote normal mitosis in the dis1-288 mutant. Suppression of the dis phenotype through loss of msc1 function requires the spindle checkpoint protein Mad2 and is limited by the presence of the heterochromatin-associated HP1 protein homolog Swi6. We speculate that alterations in histone acetylation promote a centromeric chromatin environment that compensates for compromised dis1 function by allowing for successful kinetochore-microtubule interactions that can satisfy the SAC. In cells arrested in mitosis by mutation of dis1, loss of function of epigenetic determinants such as Msc1 or specific HDACs can promote cell survival. Because the KDM5 family of proteins has been implicated in human cancers, an appreciation of the potential role of this family of proteins in chromosome segregation is warranted. KEYWORDS Msc1; lysine demethylase KDM5; histone deacetylase (HDAC); Rb; PLU-1; RBP2; trichostatin; thiabendazole; Mad2; Dis1 (XMAP215, TOG1); Swi6 (HP1 homolog) A CCURATE chromosome segregation relies on precise assembly of the multiprotein kinetochore complex, which mediates the link between chromosomes and the mitotic spindle (Przewloka and Glover 2009). The histone H3 variant CENP-A, along with epigenetic marks on canonical histones, defines centromeric chromatin, which forms the template for kinetochore assembly (Allshire and Karpen 2008;Verdaasdonk and Bloom 2011). Kinetochores serve as the site of spindle microtubule attachment (Santaguida and Musacchio 2009) and, along with the centromere, translate microtubule attachment status to mediate force balance, tension sensing, and spindle checkpoint control (Bloom 2014). When associations between chromosomes and the spindle are incorrect, the spindle assembly checkpoint (SAC) delays progression through mitosis by preventing the onset of anaphase (Musacchio and Salmon 2007;Foley and Kapoor 2013).Fission yeast centromeric chromatin (Allshire and Ekwall 2015) consists of a central core (cnt) and internal inverted repeats (imr), defined by the presence of CENP-A and methylated histone H3 K4 chromatin, flanked by heterochromatic outer repeats (otr) marked by methylated histone H3 K9 (Partridge et al. 2000;Takahashi et al. 2000;Kniola et al. 2001). The consti...

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Epigenetic Regulation of Chromatin States inSchizosaccharomyces pombe

Cited by 173 publications

References 162 publications

Accumulation of RNA on chromatin disrupts heterochromatic silencing

Accumulation of RNA on chromatin disrupts heterochromatic silencing

Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2

Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe

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