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Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells

BACKGROUND: Pathogenic mutations in WRN are a cause of premature aging disease Werner syndrome (WS). Besides accelerated aging phenotypes and cancer predisposition, patients with WS also display underdevelopment in the skeletal system, characterized by short stature, light body weight and unusually...

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Autores principales: Leung, Adrian On-Wah, Yiu, Tsz-Ching, Liu, Lingxiao, Tam, Hei-Yin, Gu, Shen, Tu, Jiajie, Pei, Duanqing, Cheung, Hoi-Hung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9805690/
https://www.ncbi.nlm.nih.gov/pubmed/36587229
http://dx.doi.org/10.1186/s13578-022-00939-8
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author Leung, Adrian On-Wah
Yiu, Tsz-Ching
Liu, Lingxiao
Tam, Hei-Yin
Gu, Shen
Tu, Jiajie
Pei, Duanqing
Cheung, Hoi-Hung
author_facet Leung, Adrian On-Wah
Yiu, Tsz-Ching
Liu, Lingxiao
Tam, Hei-Yin
Gu, Shen
Tu, Jiajie
Pei, Duanqing
Cheung, Hoi-Hung
author_sort Leung, Adrian On-Wah
collection PubMed
description BACKGROUND: Pathogenic mutations in WRN are a cause of premature aging disease Werner syndrome (WS). Besides accelerated aging phenotypes and cancer predisposition, patients with WS also display underdevelopment in the skeletal system, characterized by short stature, light body weight and unusually thin extremities. The reasons for these developmental defects are not completely understood and the underlying molecular mechanism remains to be elucidated. RESULTS: In this study, WRN was found to modulate transcription of short stature homeobox gene SHOX. Loss of WRN resulted in insufficient expression of SHOX, the gene dose of which is critical for driving chondrocyte differentiation. WRN could bind the G-quadruplex (G4) structures in the SHOX promoter and stimulate transcription. Aberrant formation of G4 structures in WRN-deficient cells impeded normal transcription of SHOX, thus resulting in impaired chondrogenesis. Chondrogenesis could be rescued by overexpression of WRN helicase or SHOX, suggesting that SHOX is a downstream target of WRN. Gene editing of the G4 structures in the SHOX promoter could increase SHOX expression, therefore rescuing the impaired chondrogenesis in WRN-deficient cells. CONCLUSIONS: Our data suggest that dysgenesis of the developing bone in WS might be caused by SHOX insufficiency. Aberrant formation of G4 structures in SHOX promoter suppresses SHOX expression and impairs chondrogenesis. Targeted mutagenesis in the G4 structures enhances SHOX expression and thus providing an opportunity to rescue the chondrogenic defect. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-022-00939-8.
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spelling pubmed-98056902023-01-02 Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells Leung, Adrian On-Wah Yiu, Tsz-Ching Liu, Lingxiao Tam, Hei-Yin Gu, Shen Tu, Jiajie Pei, Duanqing Cheung, Hoi-Hung Cell Biosci Research BACKGROUND: Pathogenic mutations in WRN are a cause of premature aging disease Werner syndrome (WS). Besides accelerated aging phenotypes and cancer predisposition, patients with WS also display underdevelopment in the skeletal system, characterized by short stature, light body weight and unusually thin extremities. The reasons for these developmental defects are not completely understood and the underlying molecular mechanism remains to be elucidated. RESULTS: In this study, WRN was found to modulate transcription of short stature homeobox gene SHOX. Loss of WRN resulted in insufficient expression of SHOX, the gene dose of which is critical for driving chondrocyte differentiation. WRN could bind the G-quadruplex (G4) structures in the SHOX promoter and stimulate transcription. Aberrant formation of G4 structures in WRN-deficient cells impeded normal transcription of SHOX, thus resulting in impaired chondrogenesis. Chondrogenesis could be rescued by overexpression of WRN helicase or SHOX, suggesting that SHOX is a downstream target of WRN. Gene editing of the G4 structures in the SHOX promoter could increase SHOX expression, therefore rescuing the impaired chondrogenesis in WRN-deficient cells. CONCLUSIONS: Our data suggest that dysgenesis of the developing bone in WS might be caused by SHOX insufficiency. Aberrant formation of G4 structures in SHOX promoter suppresses SHOX expression and impairs chondrogenesis. Targeted mutagenesis in the G4 structures enhances SHOX expression and thus providing an opportunity to rescue the chondrogenic defect. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-022-00939-8. BioMed Central 2022-12-31 /pmc/articles/PMC9805690/ /pubmed/36587229 http://dx.doi.org/10.1186/s13578-022-00939-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Leung, Adrian On-Wah
Yiu, Tsz-Ching
Liu, Lingxiao
Tam, Hei-Yin
Gu, Shen
Tu, Jiajie
Pei, Duanqing
Cheung, Hoi-Hung
Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
title Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
title_full Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
title_fullStr Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
title_full_unstemmed Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
title_short Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
title_sort targeting g-quadruplex for rescuing impaired chondrogenesis in wrn-deficient stem cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9805690/
https://www.ncbi.nlm.nih.gov/pubmed/36587229
http://dx.doi.org/10.1186/s13578-022-00939-8
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