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The establishment of HP1-independent heterochromatin reveals an essential role for HP1 proteins in maintaining epigenetic memory.

ABSTRACT: H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. A conserved class of HP1 proteins are critically required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how HP1 protein binding to heterochromatin establishes and maintains transcriptional silencing. Here, we demonstrate that the S.pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1 and an H3K14 acetyltransferase, Mst2 are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and increased spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identifies a genetically separable function in maintaining epigenetic memory.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE233333 | GEO | 2023/05/24

REPOSITORIES: GEO

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The establishment of HP1-independent heterochromatin reveals an essential role for HP1 proteins in maintaining epigenetic memory

Project description:H3K9 methylation (H3K9me) marks transcriptionally silent genomic regions called heterochromatin. A conserved class of HP1 proteins are critically required to establish and maintain heterochromatin. HP1 proteins bind to H3K9me, recruit factors that promote heterochromatin formation, and oligomerize to form phase-separated condensates. We do not understand how HP1 protein binding to heterochromatin establishes and maintains transcriptional silencing. Here, we demonstrate that the S.pombe HP1 homolog, Swi6, can be completely bypassed to establish silencing at ectopic and endogenous loci when an H3K4 methyltransferase, Set1 and an H3K14 acetyltransferase, Mst2 are deleted. Deleting Set1 and Mst2 enhances Clr4 enzymatic activity, leading to higher H3K9me levels and increased spreading. In contrast, Swi6 and its capacity to oligomerize were indispensable during epigenetic maintenance. Our results demonstrate the role of HP1 proteins in regulating histone modification crosstalk during establishment and identifies a genetically separable function in maintaining epigenetic memory.

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Project description:Heterochromatin formation in Schizosaccharomyces pombe requires the spreading of histone 3 (H3) Lysine 9 (K9) methylation (me) from nucleation centers by the H3K9 methylase, Suv39/Clr4, and the reader protein, HP1/Swi6. To accomplish this, Suv39/Clr4 and HP1/Swi6 have to associate with nucleosomes both nonspecifically, binding DNA and octamer surfaces and specifically, via recognition of methylated H3K9 by their respective chromodomains. However, how both proteins avoid competition for the same nucleosomes in this process is unclear. Here, we show that phosphorylation tunes the nucleosome affinity of HP1/Swi6 such that it preferentially partitions onto Suv39/Clr4’s trimethyl product rather than its unmethylated substrates. Preferential partitioning enables efficient conversion from di-to trimethylation on nucleosomes in vitro and H3K9me3 spreading in vivo. Together, our data suggests that phosphorylation of HP1/Swi6 creates a regime that relieves competition with the “read-write” mechanism of Suv39/Clr4 for productive heterochromatin spreading.

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Project description:Heterochromatin, a highly compact chromatin state characterized by histone H3 lysine 9 methylation (H3K9me) and HP1 protein binding, epigenetically silences the underlying DNA and influences the expression of neighboring genes. Therefore the sites of heterochromatin assembly and its subsequent spreading are generally precisely determined. Here we show that in fission yeast, the combined absence of anti-silencing factors Mst2 and Epe1 results in uncontrolled heterochromatin spreading and severe growth defects. Interestingly, these cells quickly recover by accumulating H3K9me at the clr4+ locus, which encodes the H3K9 methyltransferase essential for heterochromatin assembly, thereby leading to reduced expression of Clr4 to restrain heterochromatin spreading. Preventing H3K9me at the clr4+ locus resulted in the accumulation of H3K9me at the rik1+ locus, which encodes another component of the Clr4 complex essential for H3K9me. Our results demonstrate that promiscuous heterochromatin assembly enables fast adaptation in response to changes in chromatin landscape and illustrate a negative feedback mechanism by which cells counteract toxic heterochromatin accumulation.

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Project description:Proteins of the conserved HP1 family are elementary components of heterochromatin and are generally assumed to play a central role in creating a rigid heterochromatic network that is densely packed and inaccessible to the transcription machinery. In this study we demonstrate that the fission yeast HP1 protein Swi6 exists as a single highly dynamic population and rapidly exchanges in cis and in trans between different heterochromatic regions. Binding to methylated H3K9 or to heterochromatic RNA decelerates Swi6 mobility. We further show that Swi6 is largely dispensable to maintain heterochromatin domains. In contrast, our results disclose an unexpected role of Swi6 in demarcating constitutive heterochromatin from neighboring euchromatin. Our results are consistent with a stochastic model of heterochromatin and imply that heterochromatin is permissive for transcription throughout the cell cycle. Rather than promoting maintenance and spreading of heterochromatin, Swi6 appears to limit these processes to ensure that heterochromatin is appropriately confined.

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Project description:The highly conserved multienzyme Rix1-containing complex (hereafter referred to as the rixosome), is required for ribosomal RNA (rRNA) processing and also localizes to heterochromatin in fission yeast, but its role in heterochromatin formation is unknown. Here we report the isolation of separation of function mutations in subunits of the rixosome that abolish its physical association with Swi6/HP1 and localization to heterochromatin, but do not affect growth or rRNA processing. These mutations abolish the epigenetic inheritance of silencing and histone H3 lysine 9 methylation (H3K9me), accumulate heterochromatic RNAs, and cannot spread H3K9me and silencing away from nucleation sites into an inserted transgene. We further show that the rixosome acts upstream of the conserved 5’-3’ exoribonuclease Dhp1/XRN2 to promote heterochromatic RNA degradation. These findings reveal a new RNA degradation pathway that specifically localizes to heterochromatin to degrade nascent transcripts and enable heterochromatin spreading and inheritance.

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