Background/Purpose: Epigenetic changes contribute to the pathogenesis of rheumatoid arthritis (RA) and a comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS) has recently been described. As previous studies indicate that energy metabolism is altered in RA FLS, we hypothesize that ChIP mark changes near energy metabolism-related genes would correlate with differences in expression of these genes.

Methods: ChIP-sequencing data, for six different ChIP marks (H3K4me1, H3K4me3, H3K9me3, H3K27ac, H3K27me3, H3K36me3) from publicly available data sets from FLS derived from 11 patients with RA and 11 patients with OA were compared to identify regions with a difference in these histone modifications. Single nearest genes to regions of interest were then utilized for pathway analyses (Gene Ontology Enrichment Analysis, KEGG pathways, PANTHER classification) to determine if particular cellular processes and pathways are associated with these chromatin changes. Pathways associated with energy metabolism were enriched near a ChIP mark change commonly associated with active transcription (H3K4me3) with the use of the whole genome as a reference. To further elucidate these findings, single nearest genes associated with any ChIP mark change and metabolism were utilized for a secondary pathway analysis. Additionally, changes in transcription of genes associated with the ChIP mark changes were assessed using RNA-sequencing data from the same cells used for the ChIP-sequencing analyses.

Results: As per the unbiased pathway analysis, 4 of the 21 pathways significantly associated with changes in H3K4me3 (p<0.05) were associated with energy metabolism with the whole genome used as a background (including glucose 6-phosphate metabolic process, regulation of triglyceride biosynthetic process and arginine metabolic process). 44 different genes involved in energy metabolism were associated with a change in at least one of the ChIP marks. These 44 genes were then used in a KEGG pathway analysis. Glycolysis/Gluconeogenesis was one of the top ranked pathways with 11 out of the 44 genes involved in this pathway (adjusted p= 2.89e-21). Of the 44 genes associated with a change in a ChIP mark, glutaminase (GLS) and the cysteine/glutamate transporter SLC7A11 were two genes with significant differences in expression as per RNA-sequencing data. Of note, both genes were shown to mediate tumor metabolic reprograming and to promote cancer progression.

Conclusion: This study of RA FLS demonstrated changes in epigenetic marks of genes related to energy metabolism and suggests that these pathways can be critical in RA pathogenesis and be involved in the imprinted aggressive phenotype displayed by RA FLS compared to OA FLS. Additionally, this dataset has the potential to identify RA-specific targets that can be used to develop novel therapeutic agents.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenetic-changes-of-energy-metabolism-related-genes-in-rheumatoid-arthritis-fibroblast-like-synoviocytes/