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Epigenetics Chromatin. 2016 May 18;9:16. doi: 10.1186/s13072-016-0064-6. eCollection 2016.

Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052 Australia.
2
Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010 Australia.
3
Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010 Australia.
4
Department of Genetics, University of Melbourne, Melbourne, VIC 3010 Australia.
#
Contributed equally

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.

RESULTS:

Here 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.

CONCLUSIONS:

Here 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.

KEYWORDS:

Epigenetic silencing; H3K9 methylation; Setdb1; X inactivation

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