The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages

•Corepressor recruitment is a genome-wide feature of inflammatory enhancers•Corepressors control enhancer-silencer-promoter looping within the Ccl2 TAD•Corepressors antagonize eRNA transcription and CBP-mediated H3K27 acetylation•Ccl2 depletion in ob/ob mice supports function targeting options While role factors coactivators controlling enhancer activity chromatin structure linked to gene expression well established, involvement corepressors not. Using macrophage activation as model, we investigate here corepressor complex containing GPS2 SMRT both at locus, encoding chemokine CCL2 (MCP-1). We report that co-occupy candidate enhancers along with CBP (H3K27 acetylase) MED1 (mediator) but act antagonistically by repressing transcription-coupled acetylation. Genome editing, transcriptional interference, cistrome analysis reveals apparently related silencer elements opposite ways. 4C-seq indicates or signaling functions mechanistically similarly trigger activation. 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Finally, demonstrate antisense complex-repressed obese (ob/ob) partially reverse metaflammation insulin resistance, highlighting potential therapeutically To compare known marks performed immunoprecipitation sequencing (ChIP-seq) TF PU.1, RAW264.7 line RAW cells). largely overlapped condition (Figure 1A) treatment lipopolysaccharide (LPS; TLR4 ligand) S1A). was localized proximal (promoter) distal (enhancer) regions its bound abundantly than 1B). also super-enhancers, ranked peaks region super-enhancer S1B). specifically looked locus most GPS2-repressed mapped bone marrow-derived (BMDMs) using ChIP-seq. Co-occupancy SMRT, MED1, CBP, PU.1 two clusters 1C). Both were assay transposase-accessible (ATAC-seq) then ChIP-seq SMRT-knockdown 1D). 70% S1C). Re-analy