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).
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
-
- 3,592
- views
-
- 563
- downloads
-
- 60
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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
Candida glabrata can thrive inside macrophages and tolerate high levels of azole antifungals. These innate abilities render infections by this human pathogen a clinical challenge. How C. glabrata reacts inside macrophages and what is the molecular basis of its drug tolerance are not well understood. Here, we mapped genome-wide RNA polymerase II (RNAPII) occupancy in C. glabrata to delineate its transcriptional responses during macrophage infection in high temporal resolution. RNAPII profiles revealed dynamic C. glabrata responses to macrophages with genes of specialized pathways activated chronologically at different times of infection. We identified an uncharacterized transcription factor (CgXbp1) important for the chronological macrophage response, survival in macrophages, and virulence. Genome-wide mapping of CgXbp1 direct targets further revealed its multi-faceted functions, regulating not only virulence-related genes but also genes associated with drug resistance. Finally, we showed that CgXbp1 indeed also affects fluconazole resistance. Overall, this work presents a powerful approach for examining host-pathogen interaction and uncovers a novel transcription factor important for C. glabrata’s survival in macrophages and drug tolerance.
-
- Chromosomes and Gene Expression
- Neuroscience
Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.
