Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype

The X chromosome inactivation (XCI) is induced by Xist long non-coding RNA and protein-coding genes. However, the small non-coding RNA function in XCI remains unidentified. Our genome-wide, loss-of-function CRISPR/Cas9 screen in female fibroblasts examines the role of microRNA (miRNAs) in XCI. A striking finding is the identification of miR106a among the top candidates from 46 the screen. Loss of miR106a is accompanied by altered Xist interactome, leading to dissociation and destabilization of Xist. The XCI interference via miR106a inhibition has therapeutic implications for Rett syndrome (RTT) girls with a defective X-linked MECP2 gene. Here, we discovered that the genetic inhibition of miR106a significantly improves several facets of RTT pathology: it increases the life span, enhances locomotor activity and exploratory behavior, and diminishes breathing variabilities. Our results suggest that miR106a targeting offers a feasible therapeutic strategy for RTT and other monogenic X-linked neurodevelopmental disorders.