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A composite DNA element that functions as a maintainer required for epigenetic inheritance of heterochromatin

ABSTRACT: Epigenetic inheritance of heterochromatin requires sequence - independent propagation mechanisms and input from DNA sequence, but how DNA contributes to inheritance is not understood. Here, we identify a DNA element ( term ed the “maintainer” ) that is necessary and sufficient for epigenetic inheritance of preexisting histone H3 lysine 9 methylation (H3K9me) and heterochromatin i n the fission yeast Schizosaccharomyces pombe . In wild - type cells, d espite its requirement for maintenance of H3K9me, the maintainer cannot establish de novo gene silencing. The maintainer is a composite 1307 - base pair DNA element with binding sites for the Atf1/Pcr1 and Deb1 transcription factors and the O rigin R ecognition C omplex (ORC) and can be converted to a silencer in cells with lower rates of H3K9me turnover , suggesting that it participate s in recruiting the H3K9 methyltransferase Clr4 / Suv39h . T hese results suggest tha t histone H3K9me is only heritable when it can collaborate with maintainer - associated DNA - binding proteins that help recruit the enzyme responsible for its epigenetic deposition .

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE169537 | GEO | 2021/08/09

REPOSITORIES: GEO

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Project description:Heterochromatic DNA domains play important roles in the regulation of gene expression and maintenance of genome stability by silencing repetitive DNA elements and transposons. In organisms ranging from fission yeast to mammals, heterochromatin assembly at DNA repeats involves the activity of small noncoding RNAs (sRNAs) associated with the RNA interference (RNAi) pathway. Typically, sRNAs, originating from long noncoding RNAs transcribed from DNA repeats, guide Argonaute-containing effector complexes to complementary nascent RNAs to initiate histone H3 lysine 9 di- and tri-methylation (H3K9me2 and H3K9me3, respectively) and heterochromatin formation. H3K9me is in turn required for recruitment of RNAi to chromatin and promotes sRNA generation. However, how heterochromatin formation, which silences transcription, can proceed by a co-transcriptional mechanism that also promotes sRNA generation remains paradoxical. Here, using Clr4, the fission yeast homolog of mammalian SUV39H H3K9 methyltransferases, we designed active site mutations, which allow H3K9me2 catalysis but block the transition to H3K9me3. We show that H3K9me2 defines a functionally distinct heterochromatin state that is sufficient for RNAi-dependent co-transcriptional gene silencing (CTGS). Unlike H3K9me3 domains, which are transcriptionally silent, H3K9me2 domains are transcriptionally active, contain modifications associated with euchromatic transcription, and couple RNAi-mediated transcript degradation to the establishment of H3K9me domains. The two H3K9me states recruit reader proteins with different efficiencies, explaining their different downstream silencing functions. Furthermore, transition from H3K9me2 to H3K9me3 is required for RNAi-independent epigenetic inheritance of H3K9me domains. Our findings demonstrate that H3K9me2 and H3K9me3 define functionally distinct heterochromatin states and uncover a mechanism for formation of transcriptionally permissive heterochromatin that is compatible with its broadly conserved role in RNAi-mediated genome defense.

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A composite DNA element that functions as a maintainer required for epigenetic inheritance of heterochromatin

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