Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype
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 regula...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61092-7 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Song Lou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-576835bb226247d19a259f1d47e4fa38 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-576835bb226247d19a259f1d47e4fa382025-08-20T03:03:37ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-61092-7Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotypeSong Lou0Rachisan DJiake Tihagam1Urszula N. Wasko2Zaffar Equbal3Sanjay Venkatesan4Klaudia Braczyk5Piotr Przanowski6Bon Il Koo7Ilyas Saltani8Arjun Tushir Singh9Shibi Likhite10Samantha Powers11George M. P. R. Souza12Robert A. Maxwell13Jun Yu14Lihua J. Zhu15Mark Beenhakker16Stephen B. G. Abbott17Zhipeng Lu18Michael R. Green19Kathrin C. Meyer20Jogender Tushir-Singh21Sanchita Bhatnagar22Department of Medical Microbiology and Immunology, University of California Davis School of MedicineDepartment of Medical Microbiology and Immunology, University of California Davis School of MedicineDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineDepartment of Medical Microbiology and Immunology, University of California Davis School of MedicineDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineDepartment of Medical Microbiology and Immunology, University of California Davis School of MedicineDepartment of Biochemistry and Molecular Genetics, University of Virginia School of MedicineDepartment of Medical Microbiology and Immunology, University of California Davis School of MedicineCenter for Gene Therapy, Nationwide Children’s HospitalCenter for Gene Therapy, Nationwide Children’s HospitalDepartment of Pharmacology, University of Virginia School of MedicineThe Vincent J. Coates Proteomics/Mass Spectrometry Core Laboratory, University of CaliforniaDepartment of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical SchoolDepartment of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical SchoolDepartment of Pharmacology, University of Virginia School of MedicineDepartment of Pharmacology, University of Virginia School of MedicineUniversity of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, USC Norris Comprehensive Cancer Center, USC Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell ResearchDepartment of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical SchoolCenter for Gene Therapy, Nationwide Children’s HospitalDepartment of Medical Microbiology and Immunology, University of California Davis School of MedicineDepartment of Medical Microbiology and Immunology, University of California Davis School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-61092-7 |
| spellingShingle | 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 Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype Nature Communications |
| title | Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype |
| title_full | Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype |
| title_fullStr | Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype |
| title_full_unstemmed | Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype |
| title_short | Targeting microRNA-dependent control of X chromosome inactivation improves the Rett Syndrome phenotype |
| title_sort | targeting microrna dependent control of x chromosome inactivation improves the rett syndrome phenotype |
| url | https://doi.org/10.1038/s41467-025-61092-7 |
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