Nuclear receptor corepressors in intellectual disability and autism

Autism spectrum disorder (ASD) is characterized by neurocognitive dysfunctions, such as impaired social interaction and language learning. Gene-environmental interactions play a pivotal role in ASD pathogenesis. Nuclear receptor corepressors (NCORs) are transcription co-regulators physically associated with histone deacetylases (HDACs) and many known players in ASD etiology such as transducin β-like 1 X-linked receptor 1 (TBL1XR1) and methyl-CpG binding protein 2 (MECP2). The epigenome-modifying NCOR complex is sensitive to many ASD risk factors, including HDAC inhibitor valproic acid (VPA) and a variety of endocrine factors, xenobiotic chemicals, or metabolites that can directly bind to multiple nuclear receptors. Here we review recent studies of NCORs in neurocognition using animal models and human genetics approaches. We discuss functional interplays between NCORs and other known players in ASD etiology. It is conceivable that the NCOR complex may bridge the in utero environmental risk factors of ASD with epigenetic remodeling and can serve as a converging point for many gene-environment interactions in the pathogenesis of ASD and intellectual disability.