Distinct roles of the corepressors NCOR and SMRT in shaping the macrophage epigenome and transcriptome linked to metabolic and inflammatory pathways

The NCOR/SMRT corepressor complex is a fundamental coregulator of these mechanisms. However, the individual roles and the relative importance of the two major subunits NCOR and SMRT remain poorly understood. Here, we assessed the genome-wide roles of NCOR and SMRT in mouse macrophages by integrative analysis of cistrome, epigenome, and transcriptome. Although both corepressors exhibit genome-wide cooccupancy, their depletion revealed that SMRT primarily represses inflammation-related genes, whereas NCOR primarily represses metabolism-related genes. NCOR also activates inflammatory genes, some characteristic of tumor-associated macrophages. Corepressor depletion selectively alters chromatin accessibility, acetylation at enhancers, and the interplay with transcription factors. Both corepressors influence each other at chromatin, with SMRT superior to NCOR. Overall design: We used different methods to deplete NCOR and SMRT in macrophages and compared the resulting transcriptional changes. Using multi-omics tools, we summarized the priority and dependency relationships among different proteins within the corepressor complex in macrophages.