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Mol Cell. 2019 Aug 22;75(4):683-699.e7. doi: 10.1016/j.molcel.2019.06.034. Epub 2019 Aug 6.

The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing.

Author information

1
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. Electronic address: etchegje@newark.rutgers.edu.
2
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
4
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
5
University of North Dakota School of Medicine, Grand Forks, ND 58201, USA.
6
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
8
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: agoren@ucsd.edu.
9
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: rmostoslavsky@mgh.harvard.edu.

Abstract

Transcriptional regulation in eukaryotes occurs at promoter-proximal regions wherein transcriptionally engaged RNA polymerase II (Pol II) pauses before proceeding toward productive elongation. The role of chromatin in pausing remains poorly understood. Here, we demonstrate that the histone deacetylase SIRT6 binds to Pol II and prevents the release of the negative elongation factor (NELF), thus stabilizing Pol II promoter-proximal pausing. Genetic depletion of SIRT6 or its chromatin deficiency upon glucose deprivation causes intragenic enrichment of acetylated histone H3 at lysines 9 (H3K9ac) and 56 (H3K56ac), activation of cyclin-dependent kinase 9 (CDK9)-that phosphorylates NELF and the carboxyl terminal domain of Pol II-and enrichment of the positive transcription elongation factors MYC, BRD4, PAF1, and the super elongation factors AFF4 and ELL2. These events lead to increased expression of genes involved in metabolism, protein synthesis, and embryonic development. Our results identified SIRT6 as a Pol II promoter-proximal pausing-dedicated histone deacetylase.

KEYWORDS:

BRD4; NELF; SIRT6; chromatin; epigenetics; histone deacetylation; transcription elongation; transcriptional pausing

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