Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype
- Song Lou
- Rachisan DJiake Tihagam
- Urszula N. Wasko
- Zaffar Equbal
- Sanjay Venkatesan
- Klaudia Braczyk
- Piotr Przanowski
- Bon Il Koo
- Ilyas Saltani
- Arjun Tushir Singh
- Shibi Likhite
- Samantha Powers
- George M. P. R. Souza
- Robert A. Maxwell
- Jun Yu
- Lihua J. Zhu
- Mark Beenhakker
- Stephen B. G. Abbott
- Zhipeng Lu
- Michael R. Green
- Kathrin C. Meyer
- Jogender Tushir-Singh
- Sanchita Bhatnagar
2025-07-04
X chromosome inactivation (XCI) is induced by Xist long non-coding RNA and protein-coding genes. However, the role of small non-coding RNA function in XCI remains unidentified. Our genome-wide, loss-of-function CRISPR/Cas9 screen in female fibroblasts identified microRNAs (miRNAs) as regulators of XCI. A striking finding is the identification of miR106a among the top candidates from the screen. Loss of miR106a is accompanied by altered Xist interactome, leading to dissociation and destabilization of Xist . 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 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.