Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

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Abstract

In this review, Core et al. discuss the recent advances in our understanding of the early steps in Pol II transcription, highlighting the events and factors involved in the establishment and release of paused Pol II. They also discuss a number of unanswered questions about the regulation and function of Pol II pausing.

Abstract

Precise spatio–temporal control of gene activity is essential for organismal development, growth, and survival in a changing environment. Decisive steps in gene regulation involve the pausing of RNA polymerase II (Pol II) in early elongation, and the controlled release of paused polymerase into productive RNA synthesis. Here we describe the factors that enable pausing and the events that trigger Pol II release into the gene. We also discuss open questions in the field concerning the stability of paused Pol II, nucleosomes as obstacles to elongation, and potential roles of pausing in defining the precision and dynamics of gene expression.

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Most cited references 226

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Selective inhibition of BET bromodomains

Panagis Filippakopoulos, Jun Qi, Sarah Picaud … (2010)

Epigenetic proteins are intently pursued targets in ligand discovery. To date, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic “writers” and “erasers”. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) which binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity toward a subset of human bromodomains is explained by co-crystal structures with BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific anti-proliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof of concept for targeting protein-protein interactions of epigenetic “readers” and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

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A chromatin landmark and transcription initiation at most promoters in human cells.

Matthew Guenther, Stuart S. Levine, Laurie A. Boyer … (2007)

We describe the results of a genome-wide analysis of human cells that suggests that most protein-coding genes, including most genes thought to be transcriptionally inactive, experience transcription initiation. We found that nucleosomes with H3K4me3 and H3K9,14Ac modifications, together with RNA polymerase II, occupy the promoters of most protein-coding genes in human embryonic stem cells. Only a subset of these genes produce detectable full-length transcripts and are occupied by nucleosomes with H3K36me3 modifications, a hallmark of elongation. The other genes experience transcription initiation but show no evidence of elongation, suggesting that they are predominantly regulated at postinitiation steps. Genes encoding most developmental regulators fall into this group. Our results also identify a class of genes that are excluded from experiencing transcription initiation, at which mechanisms that prevent initiation must predominate. These observations extend to differentiated cells, suggesting that transcription initiation at most genes is a general phenomenon in human cells.

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Genome-wide mapping of in vivo protein-DNA interactions.

D Johnson, A Mortazavi, R M Myers … (2007)

In vivo protein-DNA interactions connect each transcription factor with its direct targets to form a gene network scaffold. To map these protein-DNA interactions comprehensively across entire mammalian genomes, we developed a large-scale chromatin immunoprecipitation assay (ChIPSeq) based on direct ultrahigh-throughput DNA sequencing. This sequence census method was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST, for repressor element-1 silencing transcription factor) to 1946 locations in the human genome. The data display sharp resolution of binding position [+/-50 base pairs (bp)], which facilitated our finding motifs and allowed us to identify noncanonical NRSF-binding motifs. These ChIPSeq data also have high sensitivity and specificity [ROC (receiver operator characteristic) area >/= 0.96] and statistical confidence (P <10(-4)), properties that were important for inferring new candidate interactions. These include key transcription factors in the gene network that regulates pancreatic islet cell development.

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Author and article information

Journal

Journal ID (nlm-ta): Genes Dev

Journal ID (iso-abbrev): Genes Dev

Journal ID (hwp): genesdev

Journal ID (pmc): genesdev

Journal ID (publisher-id): GAD

Title: Genes & Development

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Print): 0890-9369

ISSN (Electronic): 1549-5477

Publication date (Print): 1 August 2019

Volume: 33

Issue: 15-16

Pages: 960-982

Affiliations

[1 ]Department of Molecular and Cell Biology, Institute of Systems Genomics, University of Connecticut, Storrs, Connecticut 06269, USA;

[2 ]Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

Author notes

Corresponding authors: karen_adelman@ 123456hms.harvard.edu , leighton.core@ 123456uconn.edu

Article

Medline ID: 8711660

DOI: 10.1101/gad.325142.119

PMC ID: 6672056

PubMed ID: 31123063

SO-VID: cc764101-2893-403d-bec6-8c560d6567bb

License:

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Page count

Pages: 23

Funding

Funded by: National Institutes of Health Common Fund 4D Nucleome Program Transformative Collaborative Project Award

Award ID: TCPA-2017-ADELMAN

Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;

Promoter-proximal pausing of RNA polymerase II: a nexus of gene regulation

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Most cited references 226

Selective inhibition of BET bromodomains

A chromatin landmark and transcription initiation at most promoters in human cells.

Genome-wide mapping of in vivo protein-DNA interactions.

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