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Transcriptionally permissive heterochromatin domains emerge from fast-evolving genetic elements

ABSTRACT: Histone posttranslational modifications are a main driver for gene regulation, nevertheless, several questions remain unanswered regarding their heritability. The replisome recycles parental histones through the cell cycle, but how this is accomplished in vivo and impacts epigenetic inheritance remains unknown. Here, we show that Caenorhabditis elegans mutants with disrupted replisome-mediated histone recycling display transgenerational defects in RNAi inheritance and fertility. These strains uncovered a particular kind of heterochromatic domain that we called Corrie domains, which are located at the borders of relatively high and low H3K9me3-rich regions and contain gene and AT-rich transposable-element (TE) clusters poised for activation upon deficient H3K9me3 maintenance. Corrie domains are conserved in Mus musculus highlighting an evolutionarily conserved heterochromatic architecture that operates as a hub for regulatory diversity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE322636 | GEO | 2026/03/05

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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Transcriptionally permissive heterochromatin domains emerge from fast-evolving genetic elements

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