Uncovering MeCP2 Molecular Interactions and Functions in Brain Development

Methyl CpG binding protein 2 (MeCP2) is a known regulator of brain development. Mutations in this X-linked gene cause Severe Neonatal-Onset Encephalopathy with Microcephaly in males and the neurodevelopmental disorder Rett Syndrome in females. Causal mutations occur anywhere within MeCP2, including the understudied intervening domain. The intervening domain includes two arginine-glycine (RG) repeat sequences and a lysine rich region, both RNA binding motifs that are evidence of an RNA binding function. Few studies have investigated the potential for MeCP2 to interact with RNA; thus, how MeCP2-RNA binding impacts brain development remains unknown. MeCP2 binds various RNAs, both coding and noncoding, however, the binding regions, identity of bound RNAs, and how this binding may regulate gene expression have not been well characterized. My studies focus on identifying specific RNAs bound by MeCP2 and the role of the intervening domain of MeCP2 in brain development. I created an intervening domain deletion iPSC cell line and used directed differentiation to cerebral organoids which shows profound molecular and cellular defects in the deletion line. I hypothesize that key neuronal RNAs bind to the intervening domain of MeCP2, and that this interaction is essential for proper brain development. To test this hypothesis, Aim 1 will identify RNA sequences that bind to the intervening domain of MeCP2 and quantify alterations in RNA expression. Aim 2 will characterize phenotypic outcomes of iPSC-derived human neural cells and cerebral organoids with the MeCP2 intervening domain deletion. As mutations in MeCP2 are the genetic cause of neurodevelopmental disorders and disrupted RNA regulation is linked to abnormal neural development, my studies have important implications for MeCP2-RNA binding as potential mechanisms for neurological disorders. Project Number: 1F31NS145712-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Chelsea Drown | Institution: UNIVERSITY OF COLORADO, Boulder, CO | Award Amount: $43,614 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-V (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11390701