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

Jean-Pierre Etchegaray; Lei Zhong; Catherine Li; Telmo Henriques; Eileen Ablondi; Tomoyoshi Nakadai; Capucine Van Rechem; Christina Ferrer; Kenneth N Ross; Jee-Eun Choi; Ann Samarakkody; Fei Ji; Andrew Chang; Ruslan I Sadreyev; Sridhar Ramaswamy; Sergei Nechaev; Johnathan R Whetstine; Robert G Roeder; Karen Adelman; Alon Goren; Raul Mostoslavsky

doi:10.1016/j.molcel.2019.06.034

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

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

Authors

Jean-Pierre Etchegaray¹, Lei Zhong², Catherine Li², Telmo Henriques³, Eileen Ablondi³, Tomoyoshi Nakadai⁴, Capucine Van Rechem², Christina Ferrer², Kenneth N Ross², Jee-Eun Choi², Ann Samarakkody⁵, Fei Ji⁶, Andrew Chang², Ruslan I Sadreyev⁷, Sridhar Ramaswamy², Sergei Nechaev⁵, Johnathan R Whetstine², Robert G Roeder⁴, Karen Adelman³, Alon Goren⁸, Raul Mostoslavsky⁹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line
Gene Deletion
Histones / genetics
Histones / metabolism
Humans
Promoter Regions, Genetic*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA Polymerase II / genetics
RNA Polymerase II / metabolism*
Sirtuins / genetics
Sirtuins / metabolism*
Transcription Elongation, Genetic*
Transcription Factors / genetics
Transcription Factors / metabolism
Transcriptional Elongation Factors / genetics
Transcriptional Elongation Factors / metabolism

Substances

AFF4 protein, human
BRD4 protein, human
Cell Cycle Proteins
ELL2 protein, human
Histones
MYC protein, human
NSMF protein, human
PAF1 protein, human
Proto-Oncogene Proteins c-myc
Transcription Factors
Transcriptional Elongation Factors
RNA Polymerase II
SIRT6 protein, human
Sirtuins

Abstract

Publication types

MeSH terms

Substances

Grants and funding