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

Research output: Contribution to journalArticlepeer-review

47 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 languageEnglish
Pages (from-to)683-699.e7
JournalMolecular Cell
Volume75
Issue number4
DOIs
StatePublished - 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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