Abstract
Regulation of RNA polymerase II (Pol2) elongation in the promoter-proximal region is an important and ubiquitous control point for gene expression in metazoans. We report that transcription of the adenovirus 5 E4 region is regulated during the release of paused Pol2 into productive elongation by recruitment of the super-elongation complex, dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism that applies to ~7% of expressed protein-coding genes in primary human airway epithelial cells. We observed that a homeostatic mechanism maintains promoter, but not enhancer, H3K18/27ac in response to extensive inhibition of CBP/p300 acetyl transferase activity by the highly specific small molecule inhibitor A-485. Further, our results suggest a function for BRD4 association at enhancers in regulating paused Pol2 release at nearby promoters. Taken together, our results uncover the processes regulating transcriptional elongation by promoter region histone H3 acetylation and homeostatic maintenance of promoter, but not enhancer, H3K18/27ac in response to inhibition of CBP/p300 acetyl transferase activity.
Highlights
In addition to RNA polymerase II (Pol2) pre-initiation complex (PIC) assembly and initiation, the transition from promoter-proximal paused Pol2 to productively elongating Pol2 is an essential step in gene transcription and an important process in the overall multicomponent orchestration of gene expression in metazoans (Core et al, 2008; Seila et al, 2008; Core and Adelman, 2019)
We previously reported that CBP/p300 acetylation of H3K18 and K27 in the two to three nucleosomes spanning the transcription start site (TSS) had very different effects on distinct steps in transcription from different human adenovirus 5 (HAdV-5) early promoters (Hsu et al, 2018)
We extended our studies to the human genome, where we found that 2 hr of A-485 treatment resulted in hypoacetylation of total cell H3K18/27 to a new, extensively hypoacetylated steady state
Summary
In addition to RNA polymerase II (Pol2) pre-initiation complex (PIC) assembly and initiation, the transition from promoter-proximal paused Pol to productively elongating Pol is an essential step in gene transcription and an important process in the overall multicomponent orchestration of gene expression in metazoans (Core et al, 2008; Seila et al, 2008; Core and Adelman, 2019). AF9 and ENL YEATS domains bind to active chromatin marks H3K9ac and H4K15ac (Gates et al, 2017), and, to a lesser extent, H3K18/27ac (Li et al, 2014), and are essential for SEC-dependent activation of a luciferase reporter driven by the HIV-1 LTR (He et al, 2011) Despite these conclusions, the function of histone acetylation during the transition from promoter-proximal paused to productively elongating Pol remains incompletely understood. We found that at a subset of enhancers with greatly decreased H3K18/27ac in response to A-485 treatment, H3K9ac is sufficient for BRD4 binding and stimulation of Pol pause release Based on these results, we propose mechanisms of BRD4 and SEC recruitment by histone H3 acetylation during the transition from promoterproximal paused to productively elongating Pol and report a homeostatic process that maintains promoter H3K18/27ac
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