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<p>X chromosome inactivation (XCI) is induced by <i>Xist</i> 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 <i>Xist</i> interactome, leading to dissociation and destabilization of <i>Xist</i>. XCI interference via miR106a inhibition has therapeutic implications for Rett syndrome (RTT) girls with a defective X-linked <i>MECP2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月4日

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  • 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

摘要

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.