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The histone deacetylase SIRT6 restrains transcription elongation via promoter-proximal pausing

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE130692 | GEO | 2019/10/31

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC6907403 | biostudies-literature

The histone deacetylase SIRT6 restrains transcription elongation via promoter-proximal pausing

Project description:The histone deacetylase SIRT6 restrains transcription elongation via promoter-proximal pausing

| PRJNA540991 | ENA

The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal pausing (PRO-Seq)

Project description: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.

2019-10-31 | GSE130691 | GEO

The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (RNA-Seq)

2019-10-31 | GSE130690 | GEO

The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (ChIP-Seq)

2019-10-31 | GSE130689 | GEO

The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal pausing (PRO-Seq)

Project description:The histone deacetylase SIRT6 controls transcription elongation via promoter-proximal pausing (PRO-Seq)

| PRJNA540994 | ENA

The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (ChIP-Seq)

Project description:The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (ChIP-Seq)

| PRJNA540993 | ENA

The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (RNA-Seq)

Project description:The histone deacetylase SIRT6 controls transcription elongation via promoter- proximal pausing (RNA-Seq)

| PRJNA540995 | ENA

Topoisomerase IIα represses transcription by enforcing promoter-proximal pausing.

Project description:Accumulation of topological stress in the form of DNA supercoiling is inherent to the advance of RNA polymerase II (Pol II) and needs to be resolved by DNA topoisomerases to sustain productive transcriptional elongation. Topoisomerases are therefore considered positive facilitators of transcription. Here, we show that, in contrast to this general assumption, human topoisomerase IIα (TOP2A) activity at promoters represses transcription of immediate early genes such as c-FOS, maintaining them under basal repressed conditions. Thus, TOP2A inhibition creates a particular topological context that results in rapid release from promoter-proximal pausing and transcriptional upregulation, which mimics the typical bursting behavior of these genes in response to physiological stimulus. We therefore describe the control of promoter-proximal pausing by TOP2A as a layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription, possibly by regulating the accumulation of DNA supercoiling at promoter regions.

| S-EPMC8052185 | biostudies-literature

Promoter-proximal elongation regulates transcription in archaea.

Project description:Recruitment of RNA polymerase and initiation factors to the promoter is the only known target for transcription activation and repression in archaea. Whether any of the subsequent steps towards productive transcription elongation are involved in regulation is not known. We characterised how the basal transcription machinery is distributed along genes in the archaeon Saccharolobus solfataricus. We discovered a distinct early elongation phase where RNA polymerases sequentially recruit the elongation factors Spt4/5 and Elf1 to form the transcription elongation complex (TEC) before the TEC escapes into productive transcription. TEC escape is rate-limiting for transcription output during exponential growth. Oxidative stress causes changes in TEC escape that correlate with changes in the transcriptome. Our results thus establish that TEC escape contributes to the basal promoter strength and facilitates transcription regulation. Impaired TEC escape coincides with the accumulation of initiation factors at the promoter and recruitment of termination factor aCPSF1 to the early TEC. This suggests two possible mechanisms for how TEC escape limits transcription, physically blocking upstream RNA polymerases during transcription initiation and premature termination of early TECs.

| S-EPMC8448881 | biostudies-literature

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