Abstract
Glucocorticoids (GCs) are highly effective anti-inflammatory drugs, yet their mechanisms of action are poorly understood. GCs bind to the glucocorticoid receptor (GR), a ligand gated transcription factor that controls gene expression in numerous cell types. Here, we characterize the GR protein interactome and find the SETD1A/COMPASS H3K4 methyl transferase complex highly enriched in activated mouse macrophages. We show that SETD1A/COMPASS is recruited by GR to specific anti-inflammatory cis-regulatory elements, coinciding with H3K4 methylation dynamics at subsets of binding sites. We identify subgroups of GR target loci that display SETD1A occupancy, H3K4 mono-, di- or tri-methyl patterns, and transcriptional changes. However, our data on methylation status and COMPASS recruitment suggest that SETD1A has additional non-histone methyl transferase transcriptional functions. Setd1a loss-of-function mutagenesis studies together with RNA-Seq reveal that SETD1A/COMPASS is required for GR-mediated transcriptional regulation of specific subcategories of inflammatory genes. Here we demonstrate that SETD1A/COMPASS cooperates with GR to control the expression of a subset of macrophage target genes. We suggest that the SETD1A/COMPASS complex mediates a significant part of the anti-inflammatory potential of GCs.
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