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Hirschsprung's disease: m6A methylase VIRMA suppresses cell migration and proliferation by regulating GSK3β

Yang Yang1, Mengzhen Zhang1, Nan Li1

  • 1Department of Pediatric Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.

Pediatric Research
|April 24, 2024
PubMed
Abstract

Insights

VIRMA, a key enzyme in RNA modification, is reduced in Hirschsprung's disease (HSCR). Its downregulation impairs cell growth and movement by increasing GSK3β, contributing to HSCR development.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Developmental Biology

Background:

  • N6-methyladenosine (m6A) is the most prevalent mRNA modification in mammals, influencing diverse biological processes.
  • VIRMA, a crucial methyltransferase, plays a significant role in m6A modification.
  • The specific involvement of VIRMA in Hirschsprung's disease (HSCR) remains largely unexplored.

Purpose of the Study:

  • To investigate the functional role of VIRMA in the pathogenesis of Hirschsprung's disease (HSCR).
  • To elucidate the molecular mechanisms underlying VIRMA's function in HSCR.
  • To identify potential molecular markers for HSCR diagnosis and prognosis.

Main Methods:

  • Quantitative real-time PCR (RT-qPCR), Western blotting, and immunohistochemistry were employed to assess VIRMA and GSK3β expression in HSCR colon tissues.
  • Immunofluorescence assays were utilized to determine the cellular localization of VIRMA and GSK3β.
  • Cell proliferation and migration were evaluated using CCK8, EdU, cell migration, and wound healing assays. mRNA stability was assessed via actinomycin D assays, and m6A levels were measured colorimetrically.

Main Results:

  • VIRMA expression was significantly downregulated in the narrow-segment colon tissues of HSCR patients.
  • Suppression of VIRMA led to inhibited cell proliferation and migration.
  • VIRMA was found to stabilize GSK3β mRNA, thereby increasing GSK3β expression, which was concurrently upregulated in HSCR tissues.
  • GSK3β was identified as the mediator of VIRMA's effects on cell migration and proliferation.

Conclusions:

  • VIRMA plays a protective role in HSCR by inhibiting cell migration and proliferation through the upregulation of GSK3β.
  • Reduced VIRMA expression and elevated GSK3β levels are characteristic of HSCR and may serve as valuable molecular markers.
  • Understanding the VIRMA-GSK3β axis offers potential therapeutic targets for HSCR.

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