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HOXA cluster gene expression during osteoblast differentiation involves epigenetic control.

Rodrigo A da Silva1, Gwenny M Fuhler2, Vincent T Janmaat2

  • 1Laboratory of Bioassays and Cellular Dynamics, Department of Chemistry and Biochemistry, Institute of Biosciences, São Paulo State University - UNESP, Botucatu, São Paulo 18618-970, Brazil; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Bone
|May 5, 2019
PubMed
Summary

HOXA gene cluster expression in bone development is regulated by DNA methylation. Osteoblast differentiation upregulates most HOXA genes but downregulates HOXA7 and HOXA10 via methylation, independent of HOTAIR and HOTTIP.

Keywords:
BoneDevelopmentDifferentiationHox genesHoxA genesOsteoblast

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Epigenetics

Background:

  • The HOXA gene cluster dictates positional identity in the skeletal system.
  • Mechanisms controlling HOXA gene expression in osteoblasts are poorly understood.
  • Promoter methylation is hypothesized to regulate HOXA expression patterns.

Purpose of the Study:

  • To investigate HOXA gene cluster expression during osteogenesis.
  • To characterize the epigenetic landscape of the HOXA cluster during osteoblast differentiation.
  • To determine the role of methylation and lncRNAs in HOXA regulation.

Main Methods:

  • In vitro osteoblast differentiation from mesenchymal precursors.
  • Analysis of HOXA gene cluster expression.
  • Epigenetic profiling, focusing on promoter methylation.
  • Assessment of lncRNAs HOTAIR and HOTTIP expression and methylation.

Main Results:

  • Osteoblast formation strongly upregulates HOXA gene cluster expression, especially midcluster genes.
  • HOXA7 and HOXA10 expression are paradoxically downregulated during osteoblast differentiation.
  • Differences in HOXA gene expression correlate with promoter methylation.
  • HOTAIR and HOTTIP expression are also methylation-regulated but do not correlate with HOXA cluster expression.

Conclusions:

  • HOXA gene expression is significantly regulated by canonical methylation-dependent mechanisms during osteoblast differentiation.
  • Flanking lncRNAs HOTAIR and HOTTIP do not appear to directly modulate HOXA cluster expression in this context.
  • Epigenetic regulation via promoter methylation is a key driver of HOXA gene expression patterns in osteogenesis.