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.