The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing
| Autor: | Ruslan I. Sadreyev, Sridhar Ramaswamy, Kenneth N. Ross, Sergei Nechaev, Karen Adelman, Fei Ji, Christina M. Ferrer, Ann Samarakkody, Eileen Ablondi, Andy J. Chang, Telmo Henriques, Lei Zhong, Johnathan R. Whetstine, Jee-Eun Choi, Jean-Pierre Etchegaray, Capucine Van Rechem, Tomoyoshi Nakadai, Catherine Li, Robert G. Roeder, Raul Mostoslavsky, Alon Goren |
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| Rok vydání: | 2019 |
| Předmět: |
BRD4
Transcription Elongation Genetic Cell Cycle Proteins RNA polymerase II Biology Article Cell Line Histones Proto-Oncogene Proteins c-myc 03 medical and health sciences 0302 clinical medicine Transcriptional regulation Humans Sirtuins Negative elongation factor Promoter Regions Genetic Molecular Biology 030304 developmental biology 0303 health sciences Acetylation Cell Biology Cell biology Chromatin Elongation factor biology.protein Cyclin-dependent kinase 9 RNA Polymerase II Histone deacetylase Transcriptional Elongation Factors Gene Deletion 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Mol Cell |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2019.06.034 |
| Popis: | Transcriptional regulation in eukaryotes occurs at promoter-proximal regions wherein transcriptionally engaged RNA Polymerase II (Pol II) pauses before proceeding towards 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) -which 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. |
| Databáze: | OpenAIRE |
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