Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

Sarah K. Sasse; Margaret Gruca; Mary A. Allen; Vineela Kadiyala; Tengyao Song; Fabienne Gally; Arnav Gupta; Miles A. Pufall; Robin D. Dowell; Anthony N. Gerber

doi:10.1101/gr.248187.119

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Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

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Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

Sarah K. Sasse, Margaret Gruca, Mary A. Allen, Vineela Kadiyala, Tengyao Song, Fabienne Gally, Arnav Gupta, Miles A. Pufall, Robin D. Dowell and Anthony N. Gerber

Genome research, Vol.29(11), pp.1753-1765

11/01/2019

DOI: 10.1101/gr.248187.119

PMCID: PMC6836729

PMID: 31519741

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Abstract

The glucocorticoid receptor (NR3C1, also known as GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements has been controversial. Here, using global run-on sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 min. Many repressed regulatory regions reside within "hyper-ChIPable" genomic regions that are subject to dynamic, yet nonspecific, interactions with some antibodies. When this artifact was accounted for, we determined that transcriptional repression does not require local GR occupancy. Instead, widespread transcriptional induction through canonical GR binding sites is associated with reciprocal repression of distal TNF-regulated enhancers through a chromatin-dependent process, as evidenced by chromatin accessibility and motif displacement analysis. Simultaneously, transcriptional induction of key anti-inflammatory effectors is decoupled from primary repression through cooperation between GR and NF-kB at a subset of regulatory regions. Thus, glucocorticoids exert bimodal restraints on inflammation characterized by rapid primary transcriptional repression without local GR occupancy and secondary anti-inflammatory effects resulting from transcriptional cooperation between GR and NF-kB.

Biochemistry & Molecular Biology

Biotechnology & Applied Microbiology

Genetics & Heredity

Life Sciences & Biomedicine

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Title: Subtitle: Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression
Creators: Sarah K. Sasse - National Jewish Health
Margaret Gruca - University of Colorado Boulder
Mary A. Allen - University of Colorado Boulder
Vineela Kadiyala - National Jewish Health
Tengyao Song - National Jewish Health
Fabienne Gally - National Jewish Health
Arnav Gupta - University of Colorado Denver
Miles A. Pufall - Roy J. and Lucille A. Carver College of Medicine
Robin D. Dowell - University of Colorado Boulder
Anthony N. Gerber - University of Colorado Denver
Resource Type: Journal article
Publication Details: Genome research, Vol.29(11), pp.1753-1765
DOI: 10.1101/gr.248187.119
PMID: 31519741
PMCID: PMC6836729
NLM abbreviation: Genome Res
ISSN: 1088-9051
eISSN: 1549-5469
Publisher: Cold Spring Harbor Lab Press, Publications Dept
Number of pages: 13
Grant note: 1S10OD012300 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL109557; F32HL136197 / National Heart, Lung, and Blood Institute, NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) P30CA046934 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01GM125871 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P30CA046934 / Genomics Shared Resource of the CU Cancer Center R01GM125871 / National Institute of General Medical Sciences, NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) F32HL136197 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Language: English
Date published: 11/01/2019
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9984288734602771

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