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

Cell Reports paper from the Uhlenhaut lab


Franziska Greulich, Michael Wierer, Aikaterini Mechtidou, Omar Gonzalez-Garcia, N. Henriette Uhlenhaut (2021 Feb 9) Cell Reports 34.  https://doi.org/10.1016/j.celrep.2021.108742


Abstract cited directly from the paper:

Glucocorticoids (GCs) are effective anti-inflammatory drugs; yet, their mechanisms of action are poorly un-derstood. GCs bind to the glucocorticoid receptor (GR), a ligand-gated transcription factor controlling geneexpression in numerous cell types. Here, we  characterize GR’s protein interactome and find the SETD1A (SETdomain 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/COM-PASS is recruited by GR to specificcis-regulatory elements, coinciding with H3K4 methylation dynamics atsubsets of sites, upon treatment with lipopolysaccharide (LPS) and GCs. By chromatin immunoprecipitationsequencing (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 methylationstatus and COMPASS recruitment suggest that SETD1A has additional transcriptional functions.Setd1aloss-of-function studies reveal that SETD1A/COMPASS is required for GR-controlled transcription of subsetsof macrophage target genes. We demonstrate that the SETD1A/COMPASS complex cooperates with GR tomediate anti-inflammatory effects.