Abstract
Background The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored.ResultsHere we report the first genomic analysis of H3K9 di- and tri-methylation on the inactive X: we find they are enriched at the intergenic, gene poor regions of the inactive X, interspersed between H3K27 tri-methylation domains found in the gene dense regions. Although H3K9 methylation is predominantly non-genic, we find that depletion of H3K9 methylation via depletion of H3K9 methyltransferase Set domain bifurcated 1 (Setdb1) during the establishment of X inactivation, results in failure of silencing for around 150 genes on the inactive X. By contrast, we find a very minor role for Setdb1-mediated H3K9 methylation once X inactivation is fully established. In addition to failed gene silencing, we observed a specific failure to silence X-linked long-terminal repeat class repetitive elements.ConclusionsHere we have shown that H3K9 methylation clearly marks the murine inactive X chromosome. The role of this mark is most apparent during the establishment phase of gene silencing, with a more muted effect on maintenance of the silent state. Based on our data, we hypothesise that Setdb1-mediated H3K9 methylation plays a role in epigenetic silencing of the inactive X via silencing of the repeats, which itself facilitates gene silencing through alterations to the conformation of the whole inactive X chromosome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0064-6) contains supplementary material, which is available to authorized users.
Highlights
The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored
Our work reveals that Set domain bifurcated 1 (Setdb1)-mediated H3K9 methylation is enriched at the intergenic regions of the inactive X, yet plays an important role in epigenetic silencing at the genes on this chromosome and genome-wide
histone H3 lysine di-methylation (H3K9me2) and histone H3 lysine tri-methylation (H3K9me3) are enriched on the inactive X, predominantly at intergenic regions H3K9 methylation has controversially been associated with the mouse inactive X, based on immunofluorescence studies
Summary
The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored. X chromosome inactivation (XCI), the dosage compensation mechanism in female mammals, is one of the best-characterised epigenetic processes It provides a Keniry et al Epigenetics & Chromatin (2016) 9:16. The Xi accumulates repressive histone marks, including histone 3 lysine 27 tri-methylation (H3K27me3), which is laid down by polycomb repressive complex 2 (PRC2) [5,6,7], and histone 2A lysine 119 monoubiquitination (H2AK119ub1) by PRC1 [8,9,10,11] While these chromatin changes predominantly occur early in the time course of XCI, at least for H3K27me this mark is neither sufficient nor necessary to establish silencing [12] suggesting a gap in our understanding of epigenetic silencing on the Xi
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