PUBLICATION

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

Authors
Tian, Y., Wang, W., Lautrup, S., Zhao, H., Li, X., Law, P.W.N., Dinh, N.D., Fang, E.F., Cheung, H.H., Chan, W.Y.
ID
ZDB-PUB-220920-33
Date
2022
Source
Nature communications   13: 5456 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • DNA-Binding Proteins/metabolism
  • RecQ Helicases/genetics
  • RecQ Helicases/metabolism
  • Bone Development
  • Werner Syndrome Helicase/genetics
  • Werner Syndrome Helicase/metabolism
  • Animals
  • G-Quadruplexes*
  • Zebrafish/genetics
  • Genes, Homeobox
  • Werner Syndrome*/genetics
(all 11)
PubMed
36114168 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
Figure Gallery (9 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
sa34829
    Point Mutation
    sa41471
      Point Mutation
      1 - 2 of 2
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      Human Disease / Model
      Sequence Targeting Reagents
      No data available
      Fish
      Antibodies
      Name Type Antigen Genes Isotypes Host Organism
      Ab7-h2afxpolyclonal
        IgGRabbit
        1 - 1 of 1
        Show
        Orthology
        No data available
        Engineered Foreign Genes
        No data available
        Mapping
        No data available