Abstract

ABSTRACTWHSC1 is a histone methyltransferase (HMT) that catalyses the addition of methyl groups to lysine 36 on histone 3. In humans, WHSC1 haploinsufficiency is associated with all known cases of Wolf-Hirschhorn syndrome (WHS). The cardinal feature of WHS is a craniofacial dysmorphism, which is accompanied by sensorineural hearing loss in 15% of individuals with WHS. Here, we show that WHSC1-deficient mice display craniofacial defects that overlap with WHS, including cochlea anomalies. Although auditory hair cells are specified normally, their stereocilia hair bundles required for sound perception fail to develop the appropriate morphology. Furthermore, the orientation and cellular organisation of cochlear hair cells and their innervation are defective. These findings identify, for the first time, the likely cause of sensorineural hearing loss in individuals with WHS.

Highlights

  • Epigenetic processes, including histone modifications by specific enzymes, are crucial for controlling gene expression, but are often altered in various cancers and other disease conditions

  • Implications and future directions These results reveal an important role for WHSC1 in auditory hair cell development, during cellular organisation and stereocilia morphogenesis, and in hair cell innervation

  • The results provide new insights into the epigenetic regulation of hair cell polarity and suggest that this activity is crucial for the arrangement of cochlear hair cells and their stereocilia

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Summary

Introduction

Epigenetic processes, including histone modifications by specific enzymes, are crucial for controlling gene expression, but are often altered in various cancers and other disease conditions One such histone-modifying enzyme is Wolf-Hirschhorn syndrome candidate 1, WHSC1 ( known as NSD2 and MMSET), mutations in which cause cancer and the human disorder, Wolf-Hirschhorn syndrome (WHS; OMIM 194190). WHS is a rare condition with an estimated prevalence of 1/20,000 to 1/50,000 births and a female predilection of 2:1 (Battaglia et al, 1999; Bergemann et al, 2005; Maas et al, 2008) It is caused by the deletion of two WHS critical regions – WHSCR-1 (Wright et al, 1997) and WHSCR-2 (Zollino et al, 2003). Most of the deletions are de novo, approximately 20% of the cases arise from unbalanced chromosome

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