The Schizosaccharomyces pombe JmjC-Protein, Msc1, Prevents H2A.Z Localization in Centromeric and Subtelomeric Chromatin Domains

Buchanan, Luke; Durand-Dubief, Mickaël; Roguev, Assen; Sakalar, Cagri; Wilhelm, Brian T.; Strålfors, Annelie; Shevchenko, Anna; Aasland, Rein; Shevchenko, Andrej; Ekwall, Karl; Stewart, A. Francis

doi:10.1371/journal.pgen.1000726

Cited by 64 publications

(99 citation statements)

References 84 publications

(111 reference statements)

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“…Bdf1 is also part of the Swr1 complex that is required for the deposition of histone variant H2A.Z (Krogan et al 2003;Kobor et al 2004;Mizuguchi et al 2004), which is also involved in counteracting heterochromatin spreading (Meneghini et al 2003). There is a Bdf1 homolog in fission yeast, which is part of the fission yeast Swr1 complex (Buchanan et al 2009;Hou et al 2010). However, fission yeast Bdf1 is not involved in boundary function at IRCs (Supplemental Fig.…”

Section: The Role Of Bdf2 In Boundary Formationmentioning

confidence: 99%

Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries

et al. 2013

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Heterochromatin spreading leads to the silencing of genes within its path, and boundary elements have evolved to constrain such spreading. In fission yeast, heterochromatin at centromeres I and III is flanked by inverted repeats termed IRCs, which are required for proper boundary functions. However, the mechanisms by which IRCs prevent heterochromatin spreading are unknown. Here, we identified Bdf2, which is homologous to the mammalian bromodomain and extraterminal (BET) family double bromodomain proteins involved in diverse types of cancers, as a factor required for proper boundary function at IRCs. Bdf2 is enriched at IRCs through its interaction with the boundary protein Epe1. The bromodomains of Bdf2 recognize acetylated histone H4 tails and antagonize Sir2-mediated deacetylation of histone H4K16. Furthermore, abolishing H4K16 acetylation (H4K16ac) with an H4K16R mutation promotes heterochromatin spreading, and mimicking H4K16ac by an H4K16Q mutation blocks heterochromatin spreading at IRCs. Our results thus illustrate a mechanism of establishing chromosome boundaries at specific sites through the recruitment of a factor that protects euchromatic histone modifications. They also reveal a previously unappreciated function of H4K16ac in cooperation with H3K9 methylation to regulate heterochromatin spreading.

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Section: The Role Of Bdf2 In Boundary Formationmentioning

confidence: 99%

Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries

et al. 2013

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“…Work in the fission yeast S. pombe revealed that the loss of H2A.Z results in silencing defects at centromeres, as well as defective chromosome segregation. 55,56 Interestingly, these phenotypes were observed despite no changes in centromeric levels of CENP-A. It remains to be determined, however,…”

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confidence: 95%

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Hardy

Robert²

2010

Epigenetics

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Despite the fact that it has been intensively studied during the last decade, the function of the histone variant H2A.Z remains enigmatic. In the last few years, we and others have determined the localization of H2A.Z in various organisms. These studies have revealed that H2A.Z occupies different well defined regions in the genome. Interestingly, H2A.Z occupies the promoters and regulatory regions of active genes, as well as constitutive and facultative heterochromatin. The localization of H2A.Z on genomic regions with so diverse functions suggests that the roles of H2A.Z are multiple, only increasing the mystery around this molecule. The way H2A.Z finds its way into these regions is not fully understood but mechanisms that direct the specific incorporation of H2A.Z in promoters and enhancers have been well described. In this Point of View, we review our recent work suggesting that non-targeted incorporation, coupled to targeted depletion of H2A.Z, is a novel mechanism for localizing H2A.Z to some regions. We propose that the various functions of H2A.Z may be a consequence of the mechanism used for its incorporation, as well as its interactions with other histone variants.

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“…Further suggesting a role for Msc1 in chromatin biology, Msc1 has been found consistently as a component of the fission yeast Swr1C complex (Buchanan et al 2009;Kim et al 2009;Zofall et al 2009;Hou et al 2010;Qiu et al 2010), which facilitates the exchange of histone H2A.Z for H2A at specific chromosomal locations. Cells lacking Msc1 exhibit elevated levels of histone H3 dimethyl-K9 at pericentromeric heterochromatin, consistent with persistence of the fission yeast HP1 homolog Swi6 in this region (Lawrence and Volpe 2009).…”

Section: Discussionmentioning

confidence: 98%

“…As is true for human KDM5A (Nishibuchi et al 2014), Msc1 associates with HDAC activity (Ahmed et al 2004), although there is no evidence to date indicating that Msc1 exists in a stable physical complex with purified fission yeast HDACs Clr6, Clr3, and Sir2 (Nicolas et al 2007;Sugiyama et al 2007;Buchanan et al 2009;Wang et al 2013;Zilio et al 2014). Further suggesting a role for Msc1 in chromatin biology, Msc1 has been found consistently as a component of the fission yeast Swr1C complex (Buchanan et al 2009;Kim et al 2009;Zofall et al 2009;Hou et al 2010;Qiu et al 2010), which facilitates the exchange of histone H2A.Z for H2A at specific chromosomal locations.…”

Section: Discussionmentioning

confidence: 99%

“…Msc1 influences centromere-kinetochore function because it exhibits genetic interactions with the centromere-specific histone H3 variant CENP-A (encoded by cnp1), and the kinetochore components Mis6, a component of the CCAN, and Mis12, a component of the KMN network (Ahmed et al 2007). Msc1 is a stoichiometric component of the Swr1 complex (Buchanan et al 2009;Kim et al 2009;Zofall et al 2009;Hou et al 2010). Msc1 shares with members of the mammalian KDM5 family of proteins a similar organization of multiple conserved domains including JmjN and JmjC domains, three PHD fingers, and a C 2 C 5 zinc finger (Ahmed et al 2004;Blair et al 2011).…”

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confidence: 99%

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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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The Schizosaccharomyces pombe JmjC-Protein, Msc1, Prevents H2A.Z Localization in Centromeric and Subtelomeric Chromatin Domains

Cited by 64 publications

References 84 publications

Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries

Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

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

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