2. Academic Validation
  3. WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome

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

  • Nat Commun. 2022 Sep 16;13(1):5456. doi: 10.1038/s41467-022-33012-6.
Yuyao Tian 1,  Wuming Wang 1 2,  Sofie Lautrup 3,  Hui Zhao 1 4,  Xiang Li 5,  Patrick Wai Nok Law 1,  Ngoc-Duy Dinh 6,  Evandro Fei Fang 3,  Hoi Hung Cheung 1,  Wai-Yee Chan 7 8 9
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
  • 2 CUHK-SDU University Joint Laboratory on Reproductive Genetics, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
  • 3 Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478, Lørenskog, Norway.
  • 4 Hong Kong Branch CAS Center of Excellence for Animal Evolution and Genetics, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
  • 5 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 6 Department of Biomedical Engineering, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
  • 7 School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR. chanwy@cuhk.edu.hk.
  • 8 CUHK-SDU University Joint Laboratory on Reproductive Genetics, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR. chanwy@cuhk.edu.hk.
  • 9 Hong Kong Branch CAS Center of Excellence for Animal Evolution and Genetics, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR. chanwy@cuhk.edu.hk.
PMID: 36114168 DOI: 10.1038/s41467-022-33012-6
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.

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