WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

Tian, Yuyao; Wang, Wuming; Lautrup, Sofie; Zhao, Hui; Li, Xiang; Law, Patrick Wai Nok; Dinh, Ngoc-Duy; Fang, Evandro Fei; Cheung, Hoi Hung; Chan, Wai‐Yee

doi:10.1038/s41467-022-33012-6

Cited by 9 publications

(6 citation statements)

References 69 publications

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“…However, wrn mutation in zebrafish, which retains the shox gene orthologue during evolution, does show shorter body length and impaired chondrogenesis [ 27 ]. A recent study using zebrafish ( wrn −/− and shox −/− ) as a model also supports the role of WRN/SHOX axis in bone growth and development [ 28 ]. This raises the question of whether WRN/wrn regulates SHOX/shox in a species-dependent manner.…”

Section: Discussionmentioning

confidence: 71%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 71%

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

et al. 2022

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“…Since the discovery of the G-tetrad structure in 1962, the structures and functions of G4 in organisms have become more and more attractive. , A variety of diseases, such as cancer, nervous system disease, and chondropathy, have been found to be related to G4 structures ,, and G4 structures are potential targets for disease treatment. Many small chemical molecules that specifically target and bind to G4, named G4 ligands, have been selected to disturb G4.…”

Section: Discussionmentioning

confidence: 99%

Ratio of the Primers Used in Polymerase Chain Reaction-Stop Analysis Impacts the Resultant Banding Pattern

Xiang,

Zhang,

et al. 2023

ACS Omega

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G-quadruplex (G4), as a dynamic nucleic acid secondary structure, widely exists in organism genomes and plays regulatory roles in a variety of cellular functions. Polymerase chain reaction stop assay (PCR-Stop) is a simple, quick, and low-cost widely used method for detection of the binding between G4 and its binding compounds. Different from the common PCR approach, no double-stranded DNA template is needed in the PCR-Stop assay, in which the forward and reverse primers extend against each other in the presence of DNA polymerase to produce a single DNA product. However, unexpected results, such as two or more PCR products, are often generated, and the mechanism is unclear. We found that the ratio of pair primers significantly impacts the generation and components of PCR-Stop products, which is crucial for the interpretation of the experiment results.

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“…These findings demonstrate that deficits in DNA repair, telomere shortening, and epigenetic alterations caused by WRN loss promote premature cellular senescence [ 122 ]. Tian et al discovered that, similar to MSCs and the bone aging phenotype, WRN deficiency results in the inhibition of bone growth and short stature in vivo [ 123 ]. They further found that loss of WRN causes chondrocyte senescence characterized by increased SA-βGal + cells and upregulated p53 and p16INK4a mRNA expression and that overexpression of SHOX , a direct target of WRN , prevents the senescence phenotype in a zebrafish model.…”

Section: Cellular Senescence and Bone-sasp In Natural Aging And Prema...mentioning

confidence: 99%

“Bone-SASP” in Skeletal Aging

2023

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Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype (SASP). The SASP factors, which are heterogeneous and tissue specific, normally include chemokines, cytokines, growth factors, adhesion molecules, and lipid components that can lead to multiple age-associated disorders by eliciting local and systemic consequences. The skeleton is a highly dynamic organ that changes constantly in shape and composition. Senescent cells in bone and bone marrow produce diverse SASP factors that induce alterations of the skeleton through paracrine effects. Herein, we refer to bone cell-associated SASP as “bone-SASP.” In this review, we describe current knowledge of cellular senescence and SASP, focusing on the role of senescent cells in mediating bone pathologies during natural aging and premature aging syndromes. We also summarize the role of cellular senescence and the bone-SASP in glucocorticoids-induced bone damage. In addition, we discuss the role of bone-SASP in the development of osteoarthritis, highlighting the mechanisms by which bone-SASP drives subchondral bone changes in metabolic syndrome-associated osteoarthritis.

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WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

Cited by 9 publications

References 69 publications

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

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

Ratio of the Primers Used in Polymerase Chain Reaction-Stop Analysis Impacts the Resultant Banding Pattern

“Bone-SASP” in Skeletal Aging

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