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

Yuyao Tian, Wuming Wang, Sofie Lautrup, Hui Zhao, Xiang Li, Patrick Wai Nok Law, Ngoc-Duy Dinh, Evandro Fei Fang, Hoi Hung Cheung and Wai-Yee Chan ()
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Yuyao Tian: the Chinese University of Hong Kong
Wuming Wang: the Chinese University of Hong Kong
Sofie Lautrup: University of Oslo and Akershus University Hospital
Hui Zhao: the Chinese University of Hong Kong
Xiang Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Patrick Wai Nok Law: the Chinese University of Hong Kong
Ngoc-Duy Dinh: the Chinese University of Hong Kong
Evandro Fei Fang: University of Oslo and Akershus University Hospital
Hoi Hung Cheung: the Chinese University of Hong Kong
Wai-Yee Chan: the Chinese University of Hong Kong

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height. Zebrafish lacking wrn exhibit impairment of bone growth and have shorter body stature. We pinpoint the function of WRN to its helicase domain. We identify short-stature homeobox (SHOX) as a crucial and direct target of WRN and find that the WRN helicase core regulates the transcriptional expression of SHOX via unwinding G-quadruplexes. Consistent with this, shox−/− zebrafish exhibit impaired bone growth, while genetic overexpression of SHOX or shox expression rescues the bone developmental deficiency induced in WRN/wrn-null mutants both in vitro and in vivo. Collectively, we have identified a previously unknown function of WRN in regulating bone development and growth through the transcriptional regulation of SHOX via the WRN helicase domain, thus illuminating a possible approach for new therapeutic strategies.

Date: 2022
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DOI: 10.1038/s41467-022-33012-6

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