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 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 and Sanchita Bhatnagar ()
Additional contact information
Song Lou: University of California Davis School of Medicine
Rachisan DJiake Tihagam: University of California Davis School of Medicine
Urszula N. Wasko: University of Virginia School of Medicine
Zaffar Equbal: University of Virginia School of Medicine
Sanjay Venkatesan: University of Virginia School of Medicine
Klaudia Braczyk: University of California Davis School of Medicine
Piotr Przanowski: University of Virginia School of Medicine
Bon Koo: University of California Davis School of Medicine
Ilyas Saltani: University of Virginia School of Medicine
Arjun Tushir Singh: University of California Davis School of Medicine
Shibi Likhite: Nationwide Children’s Hospital
Samantha Powers: Nationwide Children’s Hospital
George M. P. R. Souza: University of Virginia School of Medicine
Robert A. Maxwell: University of California
Jun Yu: University of Massachusetts Medical School
Lihua J. Zhu: University of Massachusetts Medical School
Mark Beenhakker: University of Virginia School of Medicine
Stephen B. G. Abbott: University of Virginia School of Medicine
Zhipeng Lu: USC Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
Michael R. Green: University of Massachusetts Medical School
Kathrin C. Meyer: Nationwide Children’s Hospital
Jogender Tushir-Singh: University of California Davis School of Medicine
Sanchita Bhatnagar: University of California Davis School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61092-7

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