Transcriptomic analysis of RTT neurons expressing miR106a-specifc sponge

ABSTRACT: The transcriptional silencing of a mammalian X chromosome is a complex but well-coordinated epigenetic process. The induction ofXistlong non-coding RNA and several protein-coding genes triggers reversible and dynamic epigenetic events to initiate, establish, and maintain X chromosome inactivation (XCI). However, small non-coding RNA function in XCI remains unidentified. Our genome-wide CRISPR/Cas9 screen in female fibroblasts examined the role of microRNA (miRNAs) in XCI. A striking finding was the identification of miR106a among the top genes from the screen. Through multiple approaches, we show that miR106a physically interacts with the conserved repeat A region in Xist. Surprisingly, this uncanonical miR106a-RepA pairing is required for the formation of N6-methyladenosine, an epigenetic RNA base modifier, which in turn stabilizes Xist.The XCI interference via miR106a inhibition has therapeutic implications for Rett syndrome (RTT) girls with a defectiveX-linked MECP2gene. Notably, the activation of silenced Mecp2 reverses the RTT-like phenotypes in adult mice1. Here, we discovered that the genetic inhibition of miR106a expressed Mecp2 from the inactive X chromosome in the brain of Tsix-Mecp2, a female symptomatic RTT murine model. We found that miR106a inhibition in Tsix-Mecp2 female mice significantly improved several facets of RTT pathology: the life span was increased, locomotor activity and exploratory behavior were improved, and apneas and breathing variabilities were diminished. Finally, miR106a-dependent MECP2 restoration in female human post-mitotic neurons normalizes morphological and functional deficits in RTT neurons. Together, our results implicate miR106a as a regulator in the transcriptional repression of the X chromosome and suggest that miR106a targeting might offer a feasible therapeutic strategy for RTT and other monogenic X-linked neurodevelopmental disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261876 | GEO | 2025/05/01

REPOSITORIES: GEO