Setdb1-mediated H3K9 methylation is enriched on the inactive X and plays a role in its epigenetic silencing. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Keniry, Andrew; Gearing, Linden; Jansz, Natasha; Liu, Joy; Holik, Aliaksei; Hickey, Peter; Kinkel, Sarah; Moore, Darcy; Breslin, Kelsey; Chen, Kelan; Liu, Ruijie; Phillips, Catherine; Pakusch, Miha; Biben, Christine; Sheridan, Julie; Kile, Benjamin; Carmichael, Catherine; Ritchie, Matthew; Hilton, Douglas; Blewitt, Marnie
• Is Part Of: Epigenetics & chromatin. Volume 9:Issue 1(2016)
• Page Start: 1
• Page End: 20
• Publication Date: 2016-12
• Subjects: H3K9 methylation -- X inactivation -- Epigenetic silencing -- Setdb1; Epigenesis -- Periodicals; Chromatin -- Periodicals; 572.8
• DOI: 10.1186/s13072-016-0064-6
• Languages: English
• ISSNs: 1756-8935

Abstract

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.