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

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. [Display omitted] •The histone deacetylase SIRT6 binds to Pol II and promotes transcriptional pausing•SIRT6 retains NELF by deacetylating intragenically H3K9 and H3K56•Removal of SIRT6 from chromatin increases K9/K56 acetylation•Recruitment of elongation factors promotes transcriptional elongation of SIRT6 targets Historically, histone deacetylases have been described as inhibitors of transcription initiation by compacting chromatin at the transcriptional starting site. Etchegaray et al. identified the histone deacetylase SIRT6 as a critical modulator of transcriptional pausing and elongation, acting downstream of recruitment of Pol II.