Abstract
A correlation between histone acetylation and transcription has been noted for a long time, but little is known about what step(s) in the transcription cycle is influenced by acetylation. We have examined the immediate transcriptional response to histone deacetylase (HDAC) inhibition, and find that release of promoter–proximal paused RNA polymerase II (Pol II) into elongation is stimulated, whereas initiation is not. Although histone acetylation is elevated globally by HDAC inhibition, less than 100 genes respond within 10 min. These genes are highly paused, are strongly associated with the chromatin regulators NURF and Trithorax, display a greater increase in acetylation of the first nucleosomes than other genes, and become transcriptionally activated by HDAC inhibition. Among these rapidly up-regulated genes are HDAC1 (Rpd3) and subunits of HDAC-containing co-repressor complexes, demonstrating feedback regulation upon HDAC inhibition. Our results suggest that histone acetylation stimulates transcription of paused genes by release of Pol II into elongation, and that increased acetylation is not a consequence of their enhanced expression. We propose that HDACs are major regulators of Pol II pausing and that this partly explains the presence of HDACs at active genes.
Highlights
A correlation between histone acetylation and transcription was noted for the first time by Vincent Allfrey in the 1960s [1]
Using DEseq2 and a 10% false discovery rate (FDR < 0.1) to identify differential precision run-on sequencing (PRO-seq) gene body reads between control and Trichostatin A (TSA)-treated samples, we found that 96 genes were significantly up-regulated already after 10 min of histone deacetylase (HDAC) inhibition, but that no genes were down-regulated at this time-point (Figure 1A and Supplementary Table S1)
Western blots showed that both H3K27ac and H3K14ac increased approximately 1.5- to 2-fold after 10 min of TSA treatment (Figure 1E and Supplementary Figure S1D). We found that this rapid response is evolutionarily conserved, as HDAC1 and the p27 CDK inhibitor were up-regulated after 10 min of TSA-treatment in human HEK293 cells (Supplementary Figure S1E), along with elevated levels of global H3K27ac (Supplementary Figure S1F)
Summary
A correlation between histone acetylation and transcription was noted for the first time by Vincent Allfrey in the 1960s [1]. The removal of acetyl groups from the epsilonamino groups of lysine residues is believed to strengthen histone-DNA interactions by increasing the positive charge of histones, and to generate or remove specific docking surfaces for chromatin-binding proteins. This may result in decreased accessibility of nucleosomal DNA to transcription factors and the basal transcription machinery, and histone hypoacetylation is typically associated with transcriptional repression (reviewed in 4). Chromatin immunoprecipitation studies showed that some histone deacetylases occupy transcriptionally active regions more strongly than silent loci [5] This raises the possibility that histone deacetylation may promote rather than inhibit transcription in some cases [6]
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