Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 inhibition

  1. Emily Hsu
  2. Nathan R Zemke
  3. Arnold J Berk  Is a corresponding author
  1. UCLA, United States

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 (SEC), dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism that applies to ~6% 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 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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE167094.

The following data sets were generated

Article and author information

Author details

  1. Emily Hsu

    Molecular Biology Institute, UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nathan R Zemke

    Molecular Biology Institute, UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6326-5925
  3. Arnold J Berk

    Molecular Biology Institute, UCLA, Los Angeles, United States
    For correspondence
    arnold.berk@icloud.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9379-6287

Funding

Professor June Lascelle Fund

  • Arnold J Berk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Version history

  1. Received: September 28, 2020
  2. Accepted: March 10, 2021
  3. Accepted Manuscript published: March 11, 2021 (version 1)
  4. Version of Record published: March 30, 2021 (version 2)
  5. Version of Record updated: April 1, 2021 (version 3)

Copyright

© 2021, Hsu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,870
    Page views
  • 358
    Downloads
  • 15
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Emily Hsu
  2. Nathan R Zemke
  3. Arnold J Berk
(2021)
Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 inhibition
eLife 10:e63512.
https://doi.org/10.7554/eLife.63512

Further reading

    1. Chromosomes and Gene Expression
    2. Microbiology and Infectious Disease
    Abdoulie O Touray, Rishi Rajesh ... Igor Cestari
    Research Article

    African trypanosomes evade host immune clearance by antigenic variation, causing persistent infections in humans and animals. These parasites express a homogeneous surface coat of variant surface glycoproteins (VSGs). They transcribe one out of hundreds of VSG genes at a time from telomeric expression sites (ESs) and periodically change the VSG expressed by transcriptional switching or recombination. The mechanisms underlying the control of VSG switching and its developmental silencing remain elusive. We report that telomeric ES activation and silencing entail an on/off genetic switch controlled by a nuclear phosphoinositide signaling system. This system includes a nuclear phosphatidylinositol 5-phosphatase (PIP5Pase), its substrate PI(3,4,5)P3, and the repressor-activator protein 1 (RAP1). RAP1 binds to ES sequences flanking VSG genes via its DNA binding domains and represses VSG transcription. In contrast, PI(3,4,5)P3 binds to the N-terminus of RAP1 and controls its DNA binding activity. Transient inactivation of PIP5Pase results in the accumulation of nuclear PI(3,4,5)P3, which binds RAP1 and displaces it from ESs, activating transcription of silent ESs and VSG switching. The system is also required for the developmental silencing of VSG genes. The data provides a mechanism controlling reversible telomere silencing essential for the periodic switching in VSG expression and its developmental regulation.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Baira Godneeva, Maria Ninova ... Alexei Aravin
    Research Article

    The conserved family of Transcription Intermediary Factors (TIF1) proteins consists of key transcriptional regulators that control transcription of target genes by modulating chromatin state. Unlike mammals that have four TIF1 members, Drosophila only encodes one member of the family, Bonus. Bonus has been implicated in embryonic development and organogenesis and shown to regulate several signaling pathways, however, its targets and mechanism of action remained poorly understood. We found that knockdown of Bonus in early oogenesis results in severe defects in ovarian development and in ectopic expression of genes that are normally repressed in the germline, demonstrating its essential function in the ovary. Recruitment of Bonus to chromatin leads to silencing associated with accumulation of the repressive H3K9me3 mark. We show that Bonus associates with the histone methyltransferase SetDB1 and the chromatin remodeler NuRD and depletion of either component releases Bonus-induced repression. We further established that Bonus is SUMOylated at a single site at its N-terminus that is conserved among insects and this modification is indispensable for Bonus’s repressive activity. SUMOylation influences Bonus’s subnuclear localization, its association with chromatin and interaction with SetDB1. Finally, we showed that Bonus SUMOylation is mediated by the SUMO E3-ligase Su(var)2–10, revealing that although SUMOylation of TIF1 proteins is conserved between insects and mammals, both the mechanism and specific site of modification is different in the two taxa. Together, our work identified Bonus as a regulator of tissue-specific gene expression and revealed the importance of SUMOylation as a regulator of complex formation in the context of transcriptional repression.