2. Academic Validation
  3. ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex

ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex

  • Cell Rep. 2016 Oct 11;17(3):653-659. doi: 10.1016/j.celrep.2016.09.050.
Richard T Timms 1,  Iva A Tchasovnikarova 1,  Robin Antrobus 1,  Gordon Dougan 2,  Paul J Lehner 3
Affiliations

Affiliations

  • 1 Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
  • 2 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
  • 3 Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: pjl30@cam.ac.uk.
PMID: 27732843 DOI: 10.1016/j.celrep.2016.09.050
Abstract

The Histone Methyltransferase SETDB1 plays a central role in repressive chromatin processes, but the functional requirement for its binding partner ATF7IP has remained enigmatic. Here, we show that ATF7IP is essential for SETDB1 stability: nuclear SETDB1 protein is degraded by the Proteasome upon ablation of ATF7IP. As a result, ATF7IP is critical for repression that requires H3K9 trimethylation by SETDB1, including transgene silencing by the HUSH complex. Furthermore, we show that loss of ATF7IP phenocopies loss of SETDB1 in genome-wide assays. ATF7IP and SETDB1 knockout cells exhibit near-identical defects in the global deposition of H3K9me3, which results in similar dysregulation of the transcriptome. Overall, these data identify a critical functional role for ATF7IP in heterochromatin formation by regulating SETDB1 abundance in the nucleus.

Keywords

ATF7IP; H3K9me3; HUSH complex; SETDB1; epigenetic silencing; heterochromatin; histone methylation; ubiquitin-mediated degradation.

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