What question did this study set out to answer?

This research aims to explore alterations in the KDM4C gene's structure and expression in rheumatoid arthritis patients.

February 14, 2026Open Access

Rare KDM4C variants and reduced expression underlie epigenetic dysregulation in rheumatoid arthritis

Key Points

This research aims to explore alterations in the KDM4C gene's structure and expression in rheumatoid arthritis patients.
Sequenced KDM4C in rheumatoid arthritis patients.
Mapped identified variants to functional domains.
Conducted quantitative PCR to assess KDM4C expression in RA and control groups.
Analyzed molecular findings with clinical characteristics and treatment histories.
Identified a rare missense mutation (R27W) in KDM4C in one RA patient.
Detected a synonymous variant in the PHD-type2 domain.
Found significantly reduced KDM4C mRNA expression in RA patients, especially in those with treatment resistance.
Correlation established between KDM4C dysregulation and increased inflammatory gene expression.

Abstract

Abstract This study aims to investigate structural and expression-level alterations in the histone demethylase KDM4C gene in patients with rheumatoid arthritis (RA) and elucidate its role in the disease’s epigenetic basis. KDM4C sequencing was performed in RA patients, and identified variants were mapped to functional domains, including the JmjN and PHD-type2 regions. KDM4C expression was assessed by quantitative PCR in RA and control groups. Molecular findings were analyzed alongside patients’ clinical characteristics and treatment histories. A rare missense mutation (c.79 C > T, R27W) located in the JmjN domain was detected in a single patient with RA. In addition, a synonymous variant was identified in the PHD-type2 domain. The R27W variant is predicted by in silico analyses to impair protein homodimerization, while the synonymous change has been hypothesized to influence translational efficiency. Neither variant has previously been linked to RA. KDM4C mRNA expression was significantly reduced in patients with RA. This reduction was particularly evident in individuals with high CRP/ESR levels, positive RF and anti-CCP status, and treatment resistance. Taken together, the molecular and clinical findings suggest a potential functional alteration of KDM4C activity. Specifically, KDM4C may have a reduced capacity to remove repressive methylation marks on histone H3, particularly H3K9me3. These findings suggest that KDM4C dysregulation may promote a closed chromatin conformation in immune cells. This state may lead to silencing of genes involved in immune regulation and increased expression of inflammatory genes, thereby contributing to the pathogenesis of RA. KDM4C appears to be an important epigenetic regulator in RA pathogenesis. The coexistence of structural variants and decreased expression underscores its potential as a diagnostic biomarker and therapeutic target. To our knowledge, this is the first study providing integrated clinical and genetic evidence linking KDM4C dysregulation to RA.

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Cite This Study

Oner et al. (Fri,) studied this question.

synapsesocial.com/papers/699010f22ccff479cfe5744f https://doi.org/https://doi.org/10.1007/s12026-026-09751-9

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