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Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
Adrian On-Wah Leung1,2, Tsz-Ching Yiu1, Lingxiao Liu1,2
1Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
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.
Insights
Werner syndrome (WS) bone defects stem from WRN protein loss, impairing SHOX gene expression. Targeting G-quadruplex structures in the SHOX promoter can restore gene function and rescue chondrogenesis.
Area of Science:
- Molecular biology
- Genetics
- Developmental biology
Background:
- Pathogenic mutations in the WRN gene cause Werner syndrome (WS), a premature aging disorder.
- WS patients exhibit skeletal underdevelopment, including short stature and thin extremities, with unclear molecular mechanisms.
- Understanding WRN's role in skeletal development is crucial for addressing WS-related phenotypes.
Purpose of the Study:
- To elucidate the molecular mechanism underlying skeletal underdevelopment in Werner syndrome.
- To investigate the relationship between WRN, SHOX gene expression, and chondrogenesis.
- To identify potential therapeutic targets for WS-associated skeletal defects.
Main Methods:
- Investigated WRN's modulation of short stature homeobox (SHOX) gene transcription.
- Analyzed WRN binding to G-quadruplex (G4) structures in the SHOX promoter.
- Utilized gene editing to modify G4 structures and assessed chondrogenesis rescue.
Main Results:
- Loss of WRN led to insufficient SHOX expression, critical for chondrocyte differentiation.
- WRN binds G4 structures in the SHOX promoter to stimulate transcription; aberrant G4 formation impaired SHOX expression and chondrogenesis.
- Overexpression of WRN or SHOX, and gene editing of SHOX promoter G4 structures, rescued chondrogenesis in WRN-deficient cells.
Conclusions:
- SHOX insufficiency due to WRN loss is a likely cause of skeletal dysgenesis in WS.
- Aberrant G4 structures in the SHOX promoter suppress SHOX expression, impairing chondrogenesis.
- Targeting G4 structures offers a potential strategy to enhance SHOX expression and rescue chondrogenic defects in WS.
