The majority of histone acetylation is a consequence of transcription
Posted on: 18 October 2019
Preprint posted on 30 September 2019
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-020-20543-z
Categories: genetics, molecular biology
Background
Gene expression in eukaryotic cells is associated with post-translational modifications of histone proteins. One of the best-known histone modifications is lysine acetylation, which is known to be enriched at actively transcribed loci. Whilst these modifications have been well characterised for many years, it remains unclear what the functional role of histone acetylation is, or even whether it promotes transcription or is a consequence of it. In this preprint, Martin et al address some of these long-standing questions – demonstrating that transcription is required for histone acetylation.
Key findings:
RNA polymerase association with chromatin is required for histone acetylation.
The authors of this study aimed to inhibit transcription in yeast to determine whether histone acetylation was disrupted. This was achieved by the use of the chemical inhibitor 1,10pt which had previously been shown to eliminate transcription in treated cells. Upon treatment with 1,10pt a loss of RNA polymerase II (RNAPII) was observed at transcribed loci. Remarkably, a concomitant loss of six different histone acetylation marks was seen after 30mins of drug treatment (Figure 1). The authors go on to show that the loss of acetylation during ablation of transcription requires active histone deacetylases (HDAC), but inhibition of HDAC was not sufficient to restore acetylation. These data raise the possibility that rather the loss of histone acetyltransferases (HATs) is the mechanism by which histone acetylation is depleted when transcription is disrupted.
Transcription is required for HAT association with genes.
Next the authors turn their attention towards the HATs that may be responsible for RNAPII dependent histone acetylation. They demonstrate that inhibition of RNAPII causes the HAT subunit Epl1 to be mislocalised. In 1,10pt treated cells Epl1 was depleted in gene bodies, becoming newly enriched in promoter regions. In untreated cells Epl1 was found to bind to upstream regions of transcribed genes corresponding to transcription factor binding sites, indicating that Epl1 is targeted to genes by transcriptional activators. A truncated version of Epl1, thought to be unable to interact with transcriptional activators, lost this upstream localisation.
HAT activity is regulated after recruitment to chromatin.
The authors noticed that the genomic occupancy of Epl1 did not reflect the distribution of acetylated histones. Furthermore, when Epl1 was mislocalised to upstream promoter regions during inhibition of transcription, no concomitant increase in acetylation was seen at these sites. These data indicate that HAT activity is regulated downstream of recruitment.
When RNAPII accumulation at the 5’ ends of genes (as indicated by NET-seq CRAC-seq and chromatin bound RNA-seq) was compared to histone acetylation, a strong correlation was observed. These regions are thought to be loci at which RNAPII progress is slow. Sequences in transcribed genes that were thought to form more stable nucleosomes correlated with impaired transcriptional elongation (i.e. increased 5’ RNAPII enrichment) and histone acetylation indicating that these strongly positioned nucleosomes may be involved in the regulation of HAT activity.
Summary
Overall, Martin et al’s data provide compelling evidence to suggest that the majority of histone acetylation occurs as a consequence of RNAPII association with chromatin, due to loss of HAT recruitment. Whilst it remains unclear how HAT activity is regulated downstream of RNAPII, this preprint provides compelling clues as to the regulation of acetylation and transcriptional.
doi: https://doi.org/10.1242/prelights.14401
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