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Pathogenic missense mutation hotspots exist in the protein\u2019s Methyl DNA binding Domain (MBD), and the Nuclear receptor Co-Repressor (NCoR) Interaction Domain (NID), indicating these regions as critical for MeCP2 function. The NID binds to a co-repressor complex allowing transcriptional repression at target genes. A putative RNA Binding Domain (RBD) was identified that overlaps with the NID, yet the role that RNA interaction plays in MeCP2 function remains underexplored. Using cell-based and in vitro molecular assays, we validated RNA interaction at the NID\/RBD of MeCP2 both to a dsRNA probe in vitro and to the lncRNA NEAT1_2 in cells. As expected, this region did not appear to affect MeCP2-chromatin interactions; however, we found that RNA-RBD interaction precludes MeCP2-NCoR binding in cells. Taken together, we find that RNA interaction at this non-canonical RNA binding domain regulates important MeCP2-protein interactions and therefore may be a key part of the pathophysiology of Rett syndrome.<\/jats:p>","DOI":"10.1093\/hmg\/ddag031","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:38:19Z","timestamp":1776339499000},"source":"Crossref","is-referenced-by-count":2,"title":["MeCP2 NID interaction with RNA: implications for Rett syndrome-relevant protein regulation"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-4852","authenticated-orcid":false,"given":"Katrina V","family":"Good","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Victoria , 3800 Finnerty Road, Victoria, BC V8W 3P6 ,","place":["Canada"]},{"name":"Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Cantre for Addiction and Mental 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