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; Jonathan 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

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, Jonathan R. Whetstine, Robert G. Roeder, Karen Adelman, Alon GorenRaul Mostoslavsky

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48 Scopus citations

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.

Original language	English
Pages (from-to)	683-699.e7
Journal	Molecular Cell
Volume	75
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2019.06.034
State	Published - Aug 22 2019

Keywords

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

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10.1016/j.molcel.2019.06.034

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Etchegaray, J. P., Zhong, L., Li, C., Henriques, T., Ablondi, E., Nakadai, T., Van Rechem, C., Ferrer, C., Ross, K. N., Choi, J. E., Samarakkody, A., Ji, F., Chang, A., Sadreyev, R. I., Ramaswamy, S., Nechaev, S., Whetstine, J. R., Roeder, R. G., Adelman, K., ... Mostoslavsky, R. (2019). The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing. Molecular Cell, 75(4), 683-699.e7. https://doi.org/10.1016/j.molcel.2019.06.034

@article{74d3d76a17a84248986ec850195e8d89,

title = "The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing",

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

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

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = aug,

day = "22",

doi = "10.1016/j.molcel.2019.06.034",

language = "English",

volume = "75",

pages = "683--699.e7",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "4",

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Etchegaray, JP, Zhong, L, Li, C, Henriques, T, Ablondi, E, Nakadai, T, Van Rechem, C, Ferrer, C, Ross, KN, Choi, JE, Samarakkody, A, Ji, F, Chang, A, Sadreyev, RI, Ramaswamy, S, Nechaev, S, Whetstine, JR, Roeder, RG, Adelman, K, Goren, A & Mostoslavsky, R 2019, 'The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing', Molecular Cell, vol. 75, no. 4, pp. 683-699.e7. https://doi.org/10.1016/j.molcel.2019.06.034

TY - JOUR

T1 - The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing

AU - Etchegaray, Jean Pierre

AU - Zhong, Lei

AU - Li, Catherine

AU - Henriques, Telmo

AU - Ablondi, Eileen

AU - Nakadai, Tomoyoshi

AU - Van Rechem, Capucine

AU - Ferrer, Christina

AU - Ross, Kenneth N.

AU - Choi, Jee Eun

AU - Samarakkody, Ann

AU - Ji, Fei

AU - Chang, Andrew

AU - Sadreyev, Ruslan I.

AU - Ramaswamy, Sridhar

AU - Nechaev, Sergei

AU - Whetstine, Jonathan R.

AU - Roeder, Robert G.

AU - Adelman, Karen

AU - Goren, Alon

AU - Mostoslavsky, Raul

PY - 2019/8/22

Y1 - 2019/8/22

N2 - 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.

AB - 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.

KW - Acetylation

KW - Cell Cycle Proteins/genetics

KW - Cell Line

KW - Gene Deletion

KW - Histones/genetics

KW - Humans

KW - Promoter Regions, Genetic

KW - Proto-Oncogene Proteins c-myc/genetics

KW - RNA Polymerase II/genetics

KW - Sirtuins/genetics

KW - Transcription Elongation, Genetic

KW - Transcription Factors/genetics

KW - Transcriptional Elongation Factors/genetics

UR - http://www.scopus.com/inward/record.url?scp=85070867093&partnerID=8YFLogxK

UR - https://pubmed.ncbi.nlm.nih.gov/31399344/

U2 - 10.1016/j.molcel.2019.06.034

DO - 10.1016/j.molcel.2019.06.034

M3 - Article

C2 - 31399344

SN - 1097-2765

VL - 75

SP - 683-699.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

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

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Keywords

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