GSE130691
The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal  pausing (PRO-Seq)
Transcriptional regulation in eukaryotes commonly occurs at promoter-proximal  regions wherein transcriptionally engaged RNA Polymerase II (Pol II) pauses before  proceeding towards productive elongation. The roles of chromatin in this process  remains poorly understood. Here, we demonstrate that the histone deacetylase SIRT6  regulates transcription elongation by binding to Pol II and anchoring the Negative  ELongation Factor NELF, thereby preventing the release of Pol II towards elongation.  Absence of SIRT6, or conditions of glucose deprivation, lead to increased levels of  acetylated histone H3 at lysines 9 (H3K9ac) and 56 (H3K56ac), activation of the CDK9  kinase, phosphorylation of NELF and Pol II, and recruitment of the transcription factors  MYC and BRD4, the PAF1 Complex, as well as several positive elongation factors, in  turn releasing Pol II into productive elongation. Collectively, we identified SIRT6 as the  first pausing-dedicated histone deacetylase, regulating intragenic H3K9ac and  H3K56ac as critical chromatin modifications modulating transcriptional pausing and  elongation. Overall design: PRO-seq: Biological replicates were generated using WT (3 replicates) mESC cells, SIRT6-KO (3 biological replicates) and Glucose deprivation (2 replicates).