Histone deacetylation promotes transcriptional silencing at facultative heterochromatin

Watts, Beth Rosina; Wittmann, Sina; Wéry, Maxime; Gautier, Camille; Kuś, Krzysztof; Birot, Adrien; Heo, Dong-Hyuk; Kilchert, Cornelia; Morillon, Antonin; Vasiljeva, Lidia

doi:10.1093/nar/gky232

Cited by 27 publications

(21 citation statements)

References 77 publications

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“…The interplay between overlapping Mmi1-dependent mechanisms at environmentally or developmentally regulated loci remains to be determined, but it is plausible that such a system facilitates rapid fine-tuning of gene expression during abrupt changes. Whether Mmi1 affects the loading of gene silencing factors such as HDACs implicated in lncRNA-mediated silencing of genes is also unknown 46,47 .…”

Section: Discussionmentioning

confidence: 99%

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing

Xie

Thillainadesan

et al. 2019

Nat Commun

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Gene regulatory mechanisms rely on a complex network of RNA processing factors to prevent untimely gene expression. In fission yeast, the highly conserved ortholog of human ERH, called Erh1, interacts with the YTH family RNA binding protein Mmi1 to form the Erh1-Mmi1 complex (EMC) implicated in gametogenic gene silencing. However, the structural basis of EMC assembly and its functions are poorly understood. Here, we present the co-crystal structure of the EMC that consists of Erh1 homodimers interacting with Mmi1 in a 2:2 stoichiometry via a conserved molecular interface. Structure-guided mutation of the Mmi1Trp112 residue, which is required for Erh1 binding, causes defects in facultative heterochromatin assembly and gene silencing while leaving Mmi1-mediated transcription termination intact. Indeed, EMC targets masked in mmi1∆ due to termination defects are revealed in mmi1W112A. Our study delineates EMC requirements in gene silencing and identifies an ERH interface required for interaction with an RNA binding protein.

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Section: Discussionmentioning

confidence: 99%

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing

Xie

Thillainadesan

et al. 2019

Nat Commun

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“…5) suggest that Abo1 plays a different role with Clr4 in this facultative heterochromatin. A recent study showed that, despite its presence at DSR genes, Clr4 is not involved in regulating mRNA levels at normal growth temperature, whereas Set1-mediated www.nature.com/scientificreports www.nature.com/scientificreports/ deacetylation by Clr3 and other HDACs plays a key role 52 . However, loss of Clr4 in cells cultivated at 18 °C alters meiotic gene silencing but also the assembly of new facultative heterochromatin islands indicating a critical role for Clr4 at lower temperature 53 .…”

Section: Discussionmentioning

confidence: 99%

Abo1 is required for the H3K9me2 to H3K9me3 transition in heterochromatin

Dong

Oya

Zahedi

et al. 2020

Sci Rep

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Heterochromatin regulation is critical for genomic stability. Different H3K9 methylation states have been discovered, with distinct roles in heterochromatin formation and silencing. However, how the transition from H3K9me2 to H3K9me3 is controlled is still unclear. Here, we investigate the role of the conserved bromodomain AAA-ATPase, Abo1, involved in maintaining global nucleosome organisation in fission yeast. We identified several key factors involved in heterochromatin silencing that interact genetically with Abo1: histone deacetylase Clr3, H3K9 methyltransferase Clr4, and HP1 homolog Swi6. Cells lacking Abo1 cultivated at 30 °C exhibit an imbalance of H3K9me2 and H3K9me3 in heterochromatin. In abo1∆ cells, the centromeric constitutive heterochromatin has increased H3K9me2 but decreased H3K9me3 levels compared to wild-type. In contrast, facultative heterochromatin regions exhibit reduced H3K9me2 and H3K9me3 levels in abo1∆. Genome-wide analysis showed that abo1∆ cells have silencing defects in both the centromeres and subtelomeres, but not in a subset of heterochromatin islands in our condition. Thus, our work uncovers a role of Abo1 in stabilising directly or indirectly Clr4 recruitment to allow the H3K9me2 to H3K9me3 transition in heterochromatin.In eukaryotic cells, the regions of the chromatin that contain active genes are termed euchromatin, and these regions condense in mitosis to allow for chromosome segregation and decondense in interphase to allow for gene transcription 1 . The chromatin regions that remain condensed throughout the cell cycle are defined as heterochromatin regions and are transcriptionally repressed 2,3 . In general, heterochromatin can be defined molecularly by the modification of histone H3, specifically the absence of methylation on lysine 4 (H3K4me) and presence of methylation on lysine 9 (H3K9me) 4-6 . A conserved group of heterochromatin proteins, the heterochromatin protein 1 (HP1) family, specifically recognise heterochromatin regions by binding to H3K9me. Both di-and tri-methylation (H3K9me2/3) enable the binding of HP1 proteins to silence heterochromatin 7,8 . Heterochromatin regions can be further classified into constitutive and facultative heterochromatin 9,10 . Fission yeast, Schizosaccharomyces pombe, is an excellent model organism for chromatin studies because its heterochromatin organisation is similar to human cells 11,12 . Examples of constitutive heterochromatin regions in S. pombe are the pericentromeric regions that contain repetitive DNA sequences 13 . These regions are regulated by RNAi-dependent silencing machinery that involves protein Dcr1 and Ago1 14,15 . In contrast, the silencing of facultative heterochromatin, such as subtelomeric regions and heterochromatin islands, is mediated by RNAi-independent machinery that can be dynamically modulated to express genes required for the cell cycle or adaptation to the cell environment 16,17 . A subset of facultative heterochromatin islands, known as "determinant of selective removal" (DSR) islands, contain meiotic ...

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“…However, another JmjC domain protein, Lid2, interacts with H3K4 methyltransferase Set1 and H3K9 methyltransferase Clr4 to coordinate H3K4 and H3K9 methylation and functions as a pro-silencing factor [45]. While it has been widely accepted that HDACs are important for heterochromatin formation [31,46,47], and more attention has been drawn towards the roles of histone demethylases in recent years, the exact mechanisms by which these enzymes contribute to the different stages of heterochromatin assembly are still under investigation.…”

Section: Introductionmentioning

confidence: 99%

The Catalytic-Dependent and -Independent Roles of Lsd1 and Lsd2 Lysine Demethylases in Heterochromatin Formation in Schizosaccharomyces pombe

Marayati

Tucker

Cerda

et al. 2020

Cells

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In eukaryotes, heterochromatin plays a critical role in organismal development and cell fate acquisition, through regulating gene expression. The evolutionarily conserved lysine-specific demethylases, Lsd1 and Lsd2, remove mono- and dimethylation on histone H3, serving complex roles in gene expression. In the fission yeast Schizosaccharomyces pombe, null mutations of Lsd1 and Lsd2 result in either severe growth defects or inviability, while catalytic inactivation causes minimal defects, indicating that Lsd1 and Lsd2 have essential functions beyond their known demethylase activity. Here, we show that catalytic mutants of Lsd1 or Lsd2 partially assemble functional heterochromatin at centromeres in RNAi-deficient cells, while the C-terminal truncated alleles of Lsd1 or Lsd2 exacerbate heterochromatin formation at all major heterochromatic regions, suggesting that Lsd1 and Lsd2 repress heterochromatic transcripts through mechanisms both dependent on and independent of their catalytic activities. Lsd1 and Lsd2 are also involved in the establishment and maintenance of heterochromatin. At constitutive heterochromatic regions, Lsd1 and Lsd2 regulate one another and cooperate with other histone modifiers, including the class II HDAC Clr3 and the Sirtuin family protein Sir2 for gene silencing, but not with the class I HDAC Clr6. Our findings explore the roles of lysine-specific demethylases in epigenetic gene silencing at heterochromatic regions.

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Histone deacetylation promotes transcriptional silencing at facultative heterochromatin

Cited by 27 publications

References 77 publications

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing

A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing

Abo1 is required for the H3K9me2 to H3K9me3 transition in heterochromatin

The Catalytic-Dependent and -Independent Roles of Lsd1 and Lsd2 Lysine Demethylases in Heterochromatin Formation in Schizosaccharomyces pombe

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