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

被引：53

作者：

Etchegaray, Jean-Pierre ^{[1
,11
]}

Zhong, Lei ^{[1
,12
]}

Li, Catherine ^{[1
]}

Henriques, Telmo ^{[2
]}

Ablondi, Eileen ^{[2
]}

Nakadai, Tomoyoshi ^{[3
]}

Van Rechem, Capucine ^{[1
,13
]}

Ferrer, Christina ^{[1
]}

Ross, Kenneth N. ^{[1
]}

Choi, Jee-Eun ^{[1
]}

Samarakkody, Ann ^{[4
]}

Ji, Fei ^{[5
,6
]}

Chang, Andrew ^{[1
]}

Sadreyev, Ruslan, I ^{[5
,6
,7
]}

Ramaswamy, Sridhar ^{[1
,14
]}

Nechaev, Sergei ^{[4
]}

Whetstine, Johnathan R. ^{[1
,15
]}

Roeder, Robert G. ^{[3
]}

Adelman, Karen ^{[2
]}

Goren, Alon ^{[8
]}

Mostoslaysky, Raul ^{[1
,9
,10
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA

[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Rockefeller Univ, Lab Biochem & Mol Biol, New York, NY 10065 USA

[4] Univ North Dakota, Sch Med, Grand Forks, ND 58201 USA

[5] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[6] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[7] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[8] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[9] Harvard Med Sch, MGH Ctr Regenerat Med, Boston, MA 02114 USA

[10] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[11] Rutgers State Univ, Dept Biol Sci, Newark, NJ 07102 USA

[12] Fdn Med, Cambridge, MA 02141 USA

[13] Stanford Med, Dept Pathol, Stanford, CA 94305 USA

[14] Tesaro Inc, Waltham, MA 02451 USA

[15] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA

来源：

MOLECULAR CELL | 2019年 / 75卷 / 04期

基金：

美国国家科学基金会;

关键词：

RNA-POLYMERASE-II; TEFB-MEDIATED PHOSPHORYLATION; P-TEFB; PAF1; COMPLEX; HIV-1; TAT; GENOMIC INSTABILITY; POL II; N-COR; CHROMATIN; ACTIVATION;

D O I：

10.1016/j.molcel.2019.06.034

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：683 / +

页数：24

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