Corepressors

Corepressors are proteins and protein complexes that repress gene transcription by interacting with DNA-binding transcription factors and nuclear receptors rather than binding DNA directly themselves. They typically act as scaffolds that recruit chromatin-modifying enzymes and remodelers to target loci, promoting a closed chromatin state and reducing RNA polymerase II activity.

Mechanisms and representative complexes are diverse. Commonly, corepressors recruit histone deacetylases (HDACs), leading to histone deacetylation and chromatin condensation. Some corepressors function within larger repressive assemblies, such as the NCoR1 and NCoR2/SMRT complexes, which recruit HDAC3 and often rely on bridging factors like TBL1XR1/TBL1XR2. Other well-characterized corepressor systems include the CoREST complex (RCOR1–3 with LSD1 and HDAC1/2) and the NuRD complex (which combines chromatin remodeling activity with HDACs). The Groucho/TLE family serves as corepressors in diverse signaling pathways in invertebrates. In many cases, corepressors are recruited by unliganded nuclear receptors and are displaced upon ligand binding, allowing transcriptional activation.

Biological roles and significance are broad. Corepressors regulate development, cell differentiation, metabolism, and response to cellular stress. They participate in lineage specification, maintenance of cell identity, and metabolic gene programs. Dysregulation or mutation of corepressor pathways has been linked to cancers and metabolic disorders, highlighting their importance in maintaining proper gene expression programs. Corepressors are complemented by coactivators, which recruit histone acetyltransferases and other activating machinery, together shaping the dynamic regulation of transcription.