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

Author

Listed:
  • 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
    The Ohio State University)

  • Jogender Tushir-Singh

    (University of California Davis School of Medicine)

  • Sanchita Bhatnagar

    (University of California Davis School of Medicine
    University of California at Davis)

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.

Suggested Citation

  • 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, 2025. "Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61092-7
    DOI: 10.1038/s41467-025-61092-7
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