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Genome-wide Analysis of HDAC Inhibitor-mediated Modulation of microRNAs and mRNAs in B Cells Induced to Undergo Class-switch DNA Recombination and Plasma Cell Differentiation
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Lower HDAC6 mRNA expression and promoter hypomethylation are associated with RA susceptibility

Tzu-Jung Fang1, Chia-Hui Lin2, Yuan-Zhao Lin2

  • 1Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Division of Geriatrics and Gerontology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan.

Journal of the Formosan Medical Association = Taiwan Yi Zhi
|November 4, 2021
PubMed
Abstract

Insights

Lower Histone deacetylases 6 (HDAC6) mRNA expression and promoter hypomethylation are linked to rheumatoid arthritis (RA) susceptibility in patients. These findings suggest HDAC6 inhibitors may not be suitable for treating RA.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Histone deacetylases 6 (HDAC6) inhibitors show promise in rheumatoid arthritis (RA) rodent models.
  • However, reduced HDAC6 expression in RA patients' synovial fibroblasts raises concerns about inhibitor efficacy.
  • This study investigates HDAC6 mRNA expression and promoter methylation in RA patients.

Purpose of the Study:

  • To examine the role of HDAC6 mRNA expression in rheumatoid arthritis (RA).
  • To analyze HDAC6 promoter methylation patterns in RA patients.
  • To determine the association between HDAC6 expression, methylation, and RA risk.

Main Methods:

  • Extracted DNA and RNA from peripheral blood mononuclear cells (PBMCs) of 138 RA patients and 102 healthy controls.
  • Utilized pyrosequencing for HDAC6 promoter methylation analysis.
  • Employed quantitative real-time polymerase chain reaction (qRT-PCR) for HDAC6 mRNA expression quantification.

Main Results:

  • RA patients exhibited significantly lower HDAC6 mRNA expression and HDAC6 promoter hypomethylation compared to controls.
  • Specific CpG sites (-229, -225, -144, -142) in the HDAC6 promoter were hypomethylated in RA patients.
  • HDAC6 mRNA expression and promoter methylation were positively correlated and associated with RA risk.
  • HDAC6 knockdown in cell lines increased inflammatory cytokines TNF-α and IL-6.

Conclusions:

  • Lower HDAC6 mRNA expression and promoter hypomethylation characterize rheumatoid arthritis (RA) patients.
  • Both reduced HDAC6 expression and promoter hypomethylation are associated with RA susceptibility.
  • HDAC6 inhibitors may not be an appropriate therapeutic strategy for RA patients.
Keywords:
Gene expressionHDAC6MethylationRheumatoid arthritis

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