NCoR2

Nuclear receptor corepressor 2 (NCoR2), also known as SMRT (silencing mediator of retinoic acid and thyroid hormone receptors), is a transcriptional corepressor in vertebrates. It is encoded by the NCOR2 gene and functions to repress gene expression in response to unliganded nuclear receptors and other transcription factors.

Mechanism and interactions: NCoR2 is a core component of the SMRT/NCoR corepressor complex. It recruits histone deacetylase 3 (HDAC3) via its deacetylase activation domain, enabling histone deacetylation and chromatin condensation. The complex is recruited to target genes by nuclear receptors such as thyroid hormone receptor and retinoic acid receptor, as well as by other factors including REV-ERB and PPARs. The activity and targeting of the complex can be modulated by post-translational modifications of NCoR2 and by adaptor proteins such as TBL1XR1/TBL1XR2 and GPS2.

Structure and isoforms: NCoR2 contains multiple repression domains that mediate interactions with transcription factors and HDAC3, as well as SANT-like domains involved in chromatin interactions. These structural elements enable recruitment of additional co-regulators and chromatin remodelers. The NCOR2 gene produces multiple isoforms through alternative splicing, contributing to tissue- and context-specific functions.

Expression and roles: NCoR2 is broadly expressed, with notable levels in liver and brain. It participates in the regulation of development, metabolism, and circadian rhythm by controlling expression of genes involved in lipid and glucose metabolism and clock function. Postnatal and tissue-specific roles reflect the dynamic balance between repression and de-repression in hormonal signaling pathways.

Clinical and research notes: Dysregulation of NCOR2 function has been linked to metabolic disturbances and is investigated for roles in cancer and neurodevelopmental contexts, though effects are highly context-dependent. See also NCOR1 and other nuclear receptor co-repressors.