Abstract
While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates invivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases.
Highlights
The plasticity of macrophages in response to extracellular signals relies on rapid and reversible chromatin remodeling events coupled with transcriptional changes to control gene expression patterns (Glass and Natoli, 2016; Kuznetsova et al, 2020; Russell et al, 2019)
GPS2 was localized in both proximal and distal regions along with H3K27ac, further analysis of its functional recruitment revealed that GPS2 bound more abundantly to enhancers than to promoters of repressed genes (Figure 1B)
We looked into the organization of the Ccl2 locus as it is one of the most relevant GPS2-repressed genes in macrophages (Fan et al, 2016)
Summary
The plasticity of macrophages in response to extracellular signals relies on rapid and reversible chromatin remodeling events coupled with transcriptional changes to control gene expression patterns (Glass and Natoli, 2016; Kuznetsova et al, 2020; Russell et al, 2019). Our previous cistrome and epigenome profiling has revealed that the GPS2 complex occupies a majority of H3K27ac-marked macrophage enhancers (Fan et al, 2016). This includes several enhancers that potentially control the expression of Ccl but that have not yet been further characterized
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