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HDAC-mediated suppression of histone turnover promotes epigenetic stability of heterochromatin

Nature Structural & Molecular Biology volume 20, pages 547–554 (2013)Cite this article

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Abstract

Heterochromatin causes epigenetic repression that can be transmitted through multiple cell divisions. However, the mechanisms underlying silencing and stability of heterochromatin are not fully understood. We show that heterochromatin differs from euchromatin in histone turnover and identify histone deacetylase (HDAC) Clr3 as a factor required for inhibiting histone turnover across heterochromatin domains in Schizosaccharomyces pombe. Loss of RNA-interference factors, Clr4 methyltransferase or HP1 proteins involved in HDAC localization causes increased histone turnover across pericentromeric domains. Clr3 also affects histone turnover at the silent mating-type region, where it can be recruited by alternative mechanisms acting in parallel to H3K9me–HP1. Notably, the JmjC-domain protein Epe1 promotes histone exchange, and loss of Epe1 suppresses both histone turnover and defects in heterochromatic silencing. Our results suggest that heterochromatic-silencing factors preclude histone turnover to promote silencing and inheritance of repressive chromatin.

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Figure 1: Differential patterns of histone turnover define heterochromatin and euchromatin domains.
Figure 2: Clr4 and RNAi are required to suppress H3 replacement at centromeres but not at the silent mating-type locus.
Figure 3: HP1 proteins Chp2 and Swi6 cooperate to prevent nucleosome turnover across a pericentromeric loci.
Figure 4: Clr3 HDAC is required for suppression of histone-H3 exchange across heterochromatin domains.
Figure 5: Increased H3 turnover in heterochromatin mutants is not solely due to changes in RNAPII transcription.
Figure 6: The JmjC domain–containing protein Epe1 promotes histone turnover across the pericentromeric regions.
Figure 7: Clr3-dependent suppression of histone turnover correlates with epigenetic stability of heterochromatin.
Figure 8: Model showing effects of factors that affect the epigenetic stability of heterochromatin.

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Acknowledgements

We are thankful to J. Barrowman for editing the manuscript, K. Zhang, K. Yamane and E. Luk for discussions, members of the Grewal laboratory for their help and P. Russell (Scripps Research Institute, La Jolla, California, USA) for the gift of pINV1 plasmid. This work is supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute. O.A. was supported by a European Molecular Biology Organization long-term post-doctoral fellowship.

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  1. Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Ozan Aygün, Sameet Mehta & Shiv I S Grewal

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  1. Ozan Aygün
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O.A. and S.I.S.G. designed research, O.A. performed all experiments, S.M. helped with microarray probe design, and O.A. and S.I.S.G. analyzed the data and wrote the paper.

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Correspondence to Shiv I S Grewal.

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Aygün, O., Mehta, S. & Grewal, S. HDAC-mediated suppression of histone turnover promotes epigenetic stability of heterochromatin. Nat Struct Mol Biol 20, 547–554 (2013). https://doi.org/10.1038/nsmb.2565

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