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Epigenetic memory independent of symmetric histone inheritance.

ABSTRACT: Heterochromatic gene silencing is an important form of gene regulation that usually requires specific histone modifications. A popular model posits that inheritance of modified histones, especially in the form of H3-H4 tetramers, underlies inheritance of heterochromatin. Because H3-H4 tetramers are randomly distributed between daughter chromatids during DNA replication, rare occurrences of asymmetric tetramer inheritance within a heterochromatic domain would have the potential to destabilize heterochromatin. This model makes a prediction that shorter heterochromatic domains would experience unbalanced tetramer inheritance more frequently, and thereby be less stable. In contrast to this prediction, we found that shortening a heterochromatic domain in Saccharomyces had no impact on the strength of silencing nor its heritability. Additionally, we found that replisome mutations that disrupt inheritance of H3-H4 tetramers had only minor effects on heterochromatin stability. These findings suggest that histones carry little or no memory of the heterochromatin state through DNA replication.

SUBMITTER: Saxton DS

PROVIDER: S-EPMC6850775 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Epigenetic memory independent of symmetric histone inheritance.

Saxton Daniel S DS Rine Jasper J

eLife 20191015

Heterochromatic gene silencing is an important form of gene regulation that usually requires specific histone modifications. A popular model posits that inheritance of modified histones, especially in the form of H3-H4 tetramers, underlies inheritance of heterochromatin. Because H3-H4 tetramers are randomly distributed between daughter chromatids during DNA replication, rare occurrences of asymmetric tetramer inheritance within a heterochromatic domain would have the potential to destabilize het ...[more]

PMID: 31613222

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Project description:Histone post-translational modifications (PTMs) are associated with epigenetic states that form the basis for cell-type-specific gene expression1,2. Once established, histone PTMs can be maintained by positive feedback involving enzymes that recognize a pre-existing histone modification and catalyse the same modification on newly deposited histones. Recent studies suggest that in wild-type cells, histone PTM-based positive feedback is too weak to mediate epigenetic inheritance in the absence of other inputs3-7. RNA interference (RNAi)-mediated histone H3 lysine 9 methylation (H3K9me) and heterochromatin formation define a potential epigenetic inheritance mechanism in which positive feedback involving short interfering RNA (siRNA) amplification can be directly coupled to histone PTM positive feedback8-14. However, it is not known whether the coupling of these two feedback loops can maintain epigenetic silencing independently of DNA sequence and in the absence of enabling mutations that disrupt genome-wide chromatin structure or transcription15-17. Here, using the fission yeast Schizosaccharomyces pombe, we show that siRNA-induced H3K9me and silencing of a euchromatic gene can be epigenetically inherited in cis during multiple mitotic and meiotic cell divisions in wild-type cells. This inheritance involves the spreading of secondary siRNAs and H3K9me3 to the targeted gene and surrounding areas, and requires both RNAi and H3K9me, suggesting that the siRNA and H3K9me positive-feedback loops act synergistically to maintain silencing. By contrast, when maintained solely by histone PTM positive feedback, silencing is erased by H3K9 demethylation promoted by Epe1, or by interallelic interactions that occur after mating to cells containing an expressed allele even in the absence of Epe1. These findings demonstrate that the RNAi machinery can mediate transgenerational epigenetic inheritance independently of DNA sequence or enabling mutations, and reveal a role for the coupling of the siRNA and H3K9me positive-feedback loops in the protection of epigenetic alleles from erasure.

Dataset Information

Epigenetic memory independent of symmetric histone inheritance.

Publications

Epigenetic memory independent of symmetric histone inheritance.

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