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Accumulation of RNA on chromatin disrupts heterochromatic silencing

ABSTRACT: Long non-coding RNAs (lncRNAs) play a conserved role in regulating gene expression, chromatin dynamics and cell differentiation. They serve as a platform for RNA interference (RNAi)-mediated heterochromatin formation or DNA methylation in many eukaryotic organisms. We found in Schizosaccharomyces pombe, that heterochromatin is lost at transcribed regions in absence of RNA degradation, although establishment is not affected. We show that heterochromatic RNAs accumulate on chromatin, form R-loops and need to be degraded by the Ccr4-Not complex or RNAi to maintain heterochromatic silencing. The Ccr4-Not complex is localized to chromatin independently of H3K9me and degrades chromatin associated transcripts, which is required for transcriptional silencing. Overexpression of heterochromatic lncRNA at a heterochromatic locus abolishes silencing of an ade6 reporter in wild type cells. Furthermore, euchromatic lncRNA accumulate on chromatin and this regulates their transcription. Our results demonstrate that chromatin bound RNA interfere with heterochromatin organization and silencing.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE94129 | GEO | 2017/04/12

SECONDARY ACCESSION(S): PRJNA369032

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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Accumulation of RNA on chromatin disrupts heterochromatic silencing

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