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The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers.

ABSTRACT: Glucocorticoids (GCs) are effective anti-inflammatory drugs; yet, their mechanisms of action are poorly understood. GCs bind to the glucocorticoid receptor (GR), a ligand-gated transcription factor controlling gene expression in numerous cell types. Here, we characterize GR's protein interactome and find the SETD1A (SET domain containing 1A)/COMPASS (complex of proteins associated with Set1) histone H3 lysine 4 (H3K4) methyltransferase complex highly enriched in activated mouse macrophages. We show that SETD1A/COMPASS is recruited by GR to specific cis-regulatory elements, coinciding with H3K4 methylation dynamics at subsets of sites, upon treatment with lipopolysaccharide (LPS) and GCs. By chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq, we identify subsets of GR target loci that display SETD1A occupancy, H3K4 mono-, di-, or tri-methylation patterns, and transcriptional changes. However, our data on methylation status and COMPASS recruitment suggest that SETD1A has additional transcriptional functions. Setd1a loss-of-function studies reveal that SETD1A/COMPASS is required for GR-controlled transcription of subsets of macrophage target genes. We demonstrate that the SETD1A/COMPASS complex cooperates with GR to mediate anti-inflammatory effects.

SUBMITTER: Greulich F

PROVIDER: S-EPMC7873837 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers.

Greulich Franziska F Wierer Michael M Mechtidou Aikaterini A Gonzalez-Garcia Omar O Uhlenhaut N Henriette NH

Cell reports 20210201 6

Glucocorticoids (GCs) are effective anti-inflammatory drugs; yet, their mechanisms of action are poorly understood. GCs bind to the glucocorticoid receptor (GR), a ligand-gated transcription factor controlling gene expression in numerous cell types. Here, we characterize GR's protein interactome and find the SETD1A (SET domain containing 1A)/COMPASS (complex of proteins associated with Set1) histone H3 lysine 4 (H3K4) methyltransferase complex highly enriched in activated mouse macrophages. We s ...[more]

PMID: 33567280

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Project description:The vitamin D receptor (VDR) mediates the endocrine actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and autoregulates the expression of its own gene in target cells. In studies herein, we used chromatin immunoprecipitation-chip analyses to examine further the activities of 1,25(OH)(2)D(3) and to assess the consequences of VDR/retinoid X receptor heterodimer binding at the VDR gene locus. We also explored mechanisms underlying the ability of retinoic acid, dexamethasone, and the protein kinase A activator forskolin to induce VDR up-regulation as well. We confirmed two previously identified intronic 1,25(OH)(2)D(3)-inducible enhancers and discovered two additional regions, one located 6 kb upstream of the VDR transcription start site. Although RNA polymerase II was present at the transcription start site in the absence of 1,25(OH)(2)D(3), it was strikingly up-regulated at both this site and at individual enhancers in its presence. 1,25(OH)(2)D(3) also increased basal levels of H4 acetylation at these enhancers as well. Surprisingly, many of these enhancers were targets for CCAAT enhancer-binding protein-beta and runt-related transcription factor 2; a subset also bound cAMP response element binding protein, retinoic acid receptor, and glucocorticoid receptor. Unexpectedly, many of these factors were resident at the Vdr gene locus in the absence of inducer, suggesting that they might contribute to basal Vdr gene expression. Indeed, small interfering RNA down-regulation of CCAAT enhancer-binding protein-beta suppressed basal VDR expression. These regulatory activities of 1,25(OH)(2)D(3), forskolin, and dexamethasone were recapitulated in MC3T3-E1 cells stably transfected with a full-length VDR bacterial artificial chromosome (BAC) clone-luciferase reporter gene. Finally, 1,25(OH)(2)D(3) also induced accumulation of VDR and up-regulated H4 acetylation at conserved regions in the human VDR gene. These data provide important new insights into VDR gene regulation in bone cells.

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The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers.

Publications

The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers.

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