The histone chaperone FACT facilitates heterochromatin spreading by regulating histone turnover and H3K9 methylation states

Murawska, Magdalena; Greenstein, R A; Schauer, Tamás; Olsen, Karl C.F.; Ng, Henry; Ladurner, Andreas G.; Al-Sady, Bassem; Braun, Sigurd

doi:10.1016/j.celrep.2021.109944

Cited by 21 publications

(24 citation statements)

References 68 publications

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“…However, a formal possibility remains that these deacetylases function in similar ways, with the activity of Clr6 at nucleation sites masked by the activity of other HDACs. The observation that heterochromatin spreading at the MAT locus is weakly affected while gene silencing is strongly affected indicates that other pathways, such as FACT [ 38 , 56 ], may act redundantly with Clr6 in heterochromatin spreading. It is also possible that Clr6 is primarily involved in distal propagation of gene silencing via its deacetylation function, which when lost indirectly weakens heterochromatin at certain loci.…”

Section: Discussionmentioning

confidence: 99%

Local chromatin context regulates the genetic requirements of the heterochromatin spreading reaction

Greenstein

Barrales

et al. 2022

PLoS Genet

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Heterochromatin spreading, the expansion of repressive chromatin structure from sequence-specific nucleation sites, is critical for stable gene silencing. Spreading re-establishes gene-poor constitutive heterochromatin across cell cycles but can also invade gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context (i.e. euchromatic, heterochromatic) or different nucleation pathways influence heterochromatin spreading remains poorly understood. Previously, we developed a single-cell sensor in fission yeast that can separately record heterochromatic gene silencing at nucleation sequences and distal sites. Here we couple our quantitative assay to a genetic screen to identify genes encoding nuclear factors linked to the regulation of heterochromatin nucleation and the distal spreading of gene silencing. We find that mechanisms underlying gene silencing distal to a nucleation site differ by chromatin context. For example, Clr6 histone deacetylase complexes containing the Fkh2 transcription factor are specifically required for heterochromatin spreading at constitutive sites. Fkh2 recruits Clr6 to nucleation-distal chromatin sites in such contexts. In addition, we find that a number of chromatin remodeling complexes antagonize nucleation-distal gene silencing. Our results separate the regulation of heterochromatic gene silencing at nucleation versus distal sites and show that it is controlled by context-dependent mechanisms. The results of our genetic analysis constitute a broad community resource that will support further analysis of the mechanisms underlying the spread of epigenetic silencing along chromatin.

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Section: Discussionmentioning

confidence: 99%

Local chromatin context regulates the genetic requirements of the heterochromatin spreading reaction

Greenstein

Barrales

et al. 2022

PLoS Genet

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“…In support of this model, FACT has been demonstrated to suppresses the deposition of newly synthesized histone H3 in active gene bodies in budding yeast [ 82 ]. FACT also suppresses histone turnover in heterochromatin [ 145 ]. It is currently unknown if Set2 represses histone turnover in gene bodies by promoting the chaperoning (and histone recycling) activity of FACT or Spt6.…”

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

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Histone modifying enzymes play critical roles in many key cellular processes and are appealing proteins for targeting by small molecules in disease. However, while the functions of histone modifying enzymes are often linked to epigenetic regulation of the genome, an emerging theme is that these enzymes often also act by non-catalytic and/or non-epigenetic mechanisms. SETD2 (Set2 in yeast) is best known for associating with the transcription machinery and methylating histone H3 on lysine 36 (H3K36) during transcription. This well-characterized molecular function of SETD2 plays a role in fine-tuning transcription, maintaining chromatin integrity, and mRNA processing. Here we give an overview of the various molecular functions and mechanisms of regulation of H3K36 methylation by Set2/SETD2. These fundamental insights are important to understand SETD2’s role in disease, most notably in cancer in which SETD2 is frequently inactivated. SETD2 also methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2. Thus, to understand its role in disease, it is important to understand and dissect the multiple roles of SETD2 within the cell. In this review we discuss how histone methylation by Set2/SETD2 has led the way in connecting histone modifications in active regions of the genome to chromatin functions and how SETD2 is leading the way to showing that we also have to look beyond histones to truly understand the physiological role of an ‘epigenetic’ writer enzyme in normal cells and in disease.

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“…As the dynamic properties of histone H2A/H2B within heterochromatin, we also reported that the histone H2A.Z/H2B dimer contributes to this heterochromatic silencing to a certain extend [120]. Other groups have reported that FACT strongly suppresses histone turnover [121][122][123], and the mechanism by which FACT regulates nucleosomes in heterochromatin is an important aspect to be considered. To predict the means by which FACT regulates heterochromatic nucleosomes in fission yeast, we proposed a hypothetical model shown in Figure 6.…”

Section: Mechanism Of Action Of Fact On Nucleosomes Within Heterochro...mentioning

confidence: 53%

Opposing Roles of FACT for Euchromatin and Heterochromatin in Yeast

Takahata¹,

Murakami²

2023

Preprint

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DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is characterized into low-density "euchromatin" and high-density "heterochromatin", with various factors being involved in its regulation. Here, we focus on chromatin regulation and gene expression by the yeast FACT complex, which functions in both euchromatin and heterochromatin. FACT is known as a histone H2A/H2B chaperone and initially reported as an elongation factor associated with RNA polymerase II. In budding yeast, FACT activates promoter chromatin by interacting with the transcriptional activators SBF/MBF via the regulation of G1/S cell cycle genes. In fission yeast, FACT plays an important role in the formation of higher-order chromatin structures and transcriptional repression by binding to Swi6, an HP1 family protein, at heterochromatin. This FACT property, which refers to the alternate chromatin-regulation depending on the binding partner, is an interesting phenomenon. Further analysis of nucleosome regulation within heterochromatin is expected in future studies.

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The histone chaperone FACT facilitates heterochromatin spreading by regulating histone turnover and H3K9 methylation states

Cited by 21 publications

References 68 publications

Local chromatin context regulates the genetic requirements of the heterochromatin spreading reaction

Local chromatin context regulates the genetic requirements of the heterochromatin spreading reaction

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Opposing Roles of FACT for Euchromatin and Heterochromatin in Yeast

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