Identification of cell-specific epigenetic patterns associated with chondroitin sulfate treatment response in an endemic arthritis, Kashin-Beck disease

Bolun Cheng; Cuiyan Wu; Wenming Wei; Hui Niu; Yan Wen; Cheng Li; Ping Chen; Hong Chang; Zhengjun Yang; Feng Zhang

doi:10.1302/2046-3758.135.BJR-2023-0271.R1

Identification of cell-specific epigenetic patterns associated with chondroitin sulfate treatment response in an endemic arthritis, Kashin-Beck disease

Bone Joint Res. 2024 May 17;13(5):237-246. doi: 10.1302/2046-3758.135.BJR-2023-0271.R1.

Authors

Bolun Cheng^{1

2

3}, Cuiyan Wu^{1

2

3}, Wenming Wei^{1

2

3}, Hui Niu^{1

2

3}, Yan Wen^{1

2

3}, Cheng Li⁴, Ping Chen⁴, Hong Chang⁴, Zhengjun Yang⁴, Feng Zhang^{1

2

3}

Affiliations

¹ Key Laboratory of Trace Elements and Endemic Diseases (Xi'an Jiaotong University), National Health and Family Planning Commission, Xi'an, China.
² Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China.
³ Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
⁴ Research Laboratory of Kashin-Beck Disease and Keshan Disease, Shaanxi Institute for Endemic Disease Prevention and Control, Xi'an, China.

PMID: 38754865
PMCID: PMC11098597
DOI: 10.1302/2046-3758.135.BJR-2023-0271.R1

Abstract

Aims: To assess the alterations in cell-specific DNA methylation associated with chondroitin sulphate response using peripheral blood collected from Kashin-Beck disease (KBD) patients before initiation of chondroitin sulphate treatment.

Methods: Peripheral blood samples were collected from KBD patients at baseline of chondroitin sulphate treatment. Methylation profiles were generated using reduced representation bisulphite sequencing (RRBS) from peripheral blood. Differentially methylated regions (DMRs) were identified using MethylKit, while DMR-related genes were defined as those annotated to the gene body or 2.2-kilobase upstream regions of DMRs. Selected DMR-related genes were further validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to assess expression levels. Tensor composition analysis was performed to identify cell-specific differential DNA methylation from bulk tissue.

Results: This study revealed 21,060 hypermethylated and 44,472 hypomethylated DMRs, and 13,194 hypermethylated and 22,448 hypomethylated CpG islands for differential global methylation for chondroitin sulphate treatment response. A total of 12,666 DMR-related genes containing DMRs were identified in their promoter regions, such as CHL1 (false discovery rate (FDR) = 2.11 × 10^-11), RIC8A (FDR = 7.05 × 10^-4), and SOX12 (FDR = 1.43 × 10^-3). Additionally, RIC8A and CHL1 were hypermethylated in responders, while SOX12 was hypomethylated in responders, all showing decreased gene expression. The patterns of cell-specific differential global methylation associated with chondroitin sulphate response were observed. Specifically, we found that DMRs located in TESPA1 and ATP11A exhibited differential DNA methylation between responders and non-responders in granulocytes, monocytes, and B cells.

Conclusion: Our study identified cell-specific changes in DNA methylation associated with chondroitin sulphate response in KBD patients.