Gene-specific mechanisms direct Glucocorticoid Receptor-driven repression of inflammatory response genes in macrophages
- Hospital for Special Surgery, United States
- Hospital For Special Surgery, United States
- Tsinghua University, China
- The University of Texas Health Science Center at San Antonio, United States
Abstract
The Glucocorticoid Receptor (GR) potently represses macrophage-elicited inflammation, however, the underlying mechanisms remain obscure. Our genome-wide analysis in mouse macrophages reveals that pro-inflammatory paused genes, activated via global negative elongation factor (NELF) dissociation and RNA Polymerase (Pol)2 release from early elongation arrest, and non-paused genes, induced by de novo Pol2 recruitment, are equally susceptible to acute glucocorticoid repression. Moreover, in both cases the dominant mechanism involves rapid GR tethering to p65 at NF-kB binding sites. Yet, specifically at paused genes, GR activation triggers widespread promoter accumulation of NELF, with myeloid cell-specific NELF deletion conferring glucocorticoid resistance. Conversely, at non-paused genes, GR attenuates the recruitment of p300 and histone acetylation, leading to a failure to assemble BRD4 and Mediator at promoters and enhancers, ultimately blocking Pol2 initiation. Thus, GR displays no preference for a specific pro-inflammatory gene class, however, it effects repression by targeting distinct temporal events and components of transcriptional machinery.
Data availability
-
Gene-specific mechanisms direct Glucocorticoid Receptor-driven repression of inflammatory response genes in macrophagesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE110279).
Article and author information
Author details
Funding
National Institutes of Health (R01DK099087)
- Maria A Sacta
- Bowranigan Tharmalingam
- Maddalena Coppo
- David A Rollins
- Dinesh K Deochand
- Bradley Benjamin
- Yurii Chinenov
- Inez Rogatsky
National Natural Science Foundation of China (91642115)
- Li Yu
- Bin Zhang
- Xiaoyu Hu
National Natural Science Foundation of China (8151101184)
- Li Yu
- Bin Zhang
- Xiaoyu Hu
U.S. Department of Defense (PR130049)
- Bowranigan Tharmalingam
- Maddalena Coppo
- Yurii Chinenov
- Inez Rogatsky
Rheumatology Research Foundation
- David A Rollins
- Yurii Chinenov
- Inez Rogatsky
Hospital for Special Surgery David Rosensweig Genomic Center
- Maddalena Coppo
- Yurii Chinenov
- Inez Rogatsky
Ministry of Science and Technology of the People's Republic of China
- Li Yu
- Bin Zhang
- Xiaoyu Hu
National Natural Science Foundation of China (81422019)
- Li Yu
- Bin Zhang
- Xiaoyu Hu
Tsinghua University
- Li Yu
- Bin Zhang
- Xiaoyu Hu
National Institutes of Health (R01 CA220578)
- Rong Li
National Natural Science Foundation of China (81571580)
- Li Yu
- Bin Zhang
- Xiaoyu Hu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Mice were maintained in the Weill Cornell Animal Facility in compliance with guidelines from the Weill Cornell Animal Care and Use Committee (Protocol approval # 2015-0050).
Reviewing Editor
- Peter Tontonoz, University of California, Los Angeles, United States
Publication history
- Received: January 7, 2018
- Accepted: January 28, 2018
- Accepted Manuscript published: February 9, 2018 (version 1)
- Version of Record published: February 21, 2018 (version 2)
Copyright
© 2018, Sacta 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
-
- 3,014
- Page views
-
- 452
- Downloads
-
- 31
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
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)
Gene-specific mechanisms direct Glucocorticoid Receptor-driven repression of inflammatory response genes in macrophages
eLife 7:e34864.
https://doi.org/10.7554/eLife.34864
Further reading
-
- Chromosomes and Gene Expression
- Microbiology and Infectious Disease
Mosquitoes transmit numerous pathogens, but large gaps remain in our understanding of their physiology. To facilitate explorations of mosquito biology, we have created Aegypti-Atlas (http://aegyptiatlas.buchonlab.com/), an online resource hosting RNAseq profiles of Ae. aegypti body parts (head, thorax, abdomen, gut, Malpighian tubules, ovaries), gut regions (crop, proventriculus, anterior and posterior midgut, hindgut), and a gut time course of blood meal digestion. Using Aegypti-Atlas, we provide insights into regionalization of gut function, blood feeding response, and immune defenses. We find that the anterior and posterior midgut possess digestive specializations which are preserved in the blood-fed state. Blood feeding initiates the sequential induction and repression/depletion of multiple cohorts of peptidases. With respect to defense, immune signaling components, but not recognition or effector molecules, show enrichment in ovaries. Basal expression of antimicrobial peptides is dominated by holotricin and gambicin, which are expressed in carcass and digestive tissues, respectively, in a mutually exclusive manner. In the midgut, gambicin and other effectors are almost exclusively expressed in the anterior regions, while the posterior midgut exhibits hallmarks of immune tolerance. Finally, in a cross-species comparison between Ae. aegypti and Anopheles gambiae midguts, we observe that regional digestive and immune specializations are conserved, indicating that our dataset may be broadly relevant to multiple mosquito species. We demonstrate that the expression of orthologous genes is highly correlated, with the exception of a ‘species signature’ comprising a few highly/disparately expressed genes. With this work, we show the potential of Aegypti-Atlas to unlock a more complete understanding of mosquito biology.
-
- Chromosomes and Gene Expression
- Genetics and Genomics
For some inducible genes, the rate and molecular mechanism of transcriptional activation depends on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation and requires both changes in chromatin structure and recruitment of poised RNA Polymerase II (RNAPII) to the promoter. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication.
