Wolf-Hirschhorn Syndrome Candidate 1 (Whsc1) Methyltransferase Signals Via a Pitx2-miR-23/24 Axis to Effect Tooth Development

Dan Su; Steve Eliason; Zhao Sun; Fan Shao; Brad A Amendt

doi:10.1016/j.jbc.2023.105324

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Wolf-Hirschhorn Syndrome Candidate 1 (Whsc1) Methyltransferase Signals Via a Pitx2-miR-23/24 Axis to Effect Tooth Development

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Wolf-Hirschhorn Syndrome Candidate 1 (Whsc1) Methyltransferase Signals Via a Pitx2-miR-23/24 Axis to Effect Tooth Development

Dan Su, Steve Eliason, Zhao Sun, Fan Shao and Brad A Amendt

The Journal of biological chemistry, Vol.299(11), 105324

11/2023

DOI: 10.1016/j.jbc.2023.105324

PMCID: PMC10656234

PMID: 37806494

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Abstract

Wolf-Hirschhorn syndrome (WHS) is a developmental disorder attributed to a partial deletion on the short arm of chromosome 4. WHS patients suffer from oral manifestations including cleft lip and palate (CLP), hypodontia, and taurodontism. Wolf-Hirschhorn syndrome candidate 1 gene (WHSC1) is a H3K36-specific methyltransferase that is deleted in every reported case of WHS. Mutation in this gene also results in tooth anomalies in patients. However, the correlation between genetic abnormalities and the tooth anomalies has remained controversial. In our study, we aimed to clarify the role of WHSC1 in tooth development. We profiled the Whsc1 expression pattern during mouse incisor and molar development by immunofluorescence staining and found Whsc1 expression is reduced as tooth development proceeds. Using RT-qPCR, Western blot, ChIP and luciferase assays, we determined that Whsc1 and Pitx2, the initial transcription factor involved in tooth development, positively and reciprocally regulate each other through their gene promoters. MicroRNAs are known to regulate gene expression post-transcriptionally during development. We previously reported miR-23a/b and miR-24-1/2 were highly expressed in the mature tooth germ. Interestingly, we demonstrate here that these two miRs directly target Whsc1 and repress its expression. Additionally, this miR cluster is also negatively regulated by Pitx2. We show the expression of these two miRs and Whsc1 are inversely correlated during mouse mandibular development. Taken together, our results provide new insights into the potential role of Whsc1 in regulating tooth development and a possible molecular mechanism underlying the dental defects in WHS.

Details

Title: Subtitle: Wolf-Hirschhorn Syndrome Candidate 1 (Whsc1) Methyltransferase Signals Via a Pitx2-miR-23/24 Axis to Effect Tooth Development
Creators: Dan Su - University of Iowa
Steve Eliason - University of Iowa
Zhao Sun - Washington University in St. Louis
Fan Shao - University of Iowa
Brad A Amendt - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.299(11), 105324
DOI: 10.1016/j.jbc.2023.105324
PMID: 37806494
PMCID: PMC10656234
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: DOI: 10.13039/100000072, name: NIDCR, award: DE028527; DOI: 10.13039/100008893, name: University of Iowa; DOI: 10.13039/100000002, name: National Institutes of Health
Language: English
Electronic publication date: 10/06/2023
Date published: 11/2023
Academic Unit: Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984476422102771

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