Epigenomic Analysis Uncovers Link Between Rheumatoid Arthritis and Huntington Disease

In their study published in Nature Communications, the authors mapped out the epigenomic profiles of rheumatoid arthritis (RA) and osteoarthritis for the first time to provide insight on RA-specific pathways and transcription factor motifs. A surprising discovery was that the Huntingtin-interacting protein-1 may play a role in the pathogenesis of RA.

Epigenomic testing is a novel approach that may lead to a greater understanding of many diseases. In a study published in Nature Communications, Ai et al use the EpiSig, an analytic tool used to detect epigenetic changes, to map out the epigenomic landscape of rheumatoid arthritis (RA) in hopes of discovering new therapeutic pathways and targets.

Despite current pharmacologic therapies designed to manage RA—a chronic inflammatory disorder that causes synovial inflammation and swelling of joints—a percentage of patients remain unresponsive and progress to disability. An area of growing interest among scientists is epigenomic testing. By mapping out the epigenomic landscape of RA, scientists hope to gain insight on disease origins as well as new cell signaling pathways.

In their study, Ai et al mapped out the epigenomic profiles of RA and osteoarthritis (OA) for the first time to provide insight on RA-specific pathways and transcription factor motifs.

The EpiSig was used to analyze diverse epigenomic data presented from RA and OA patient samples. Histone modifications, whole-genome bisulfite sequencing, RNA sequencing, and transposase-accessible chromatin with high-throughput sequencing were all integrated to define the epigenomic landscape of RA. When comparing the epigenetic marking of RA and OA samples, a total of 31,969 differently modified epigenetic regions (DMER) were found across 125 clusters. Three-hundred and thirty-nine differently expressed genes were also identified between the 2 conditions, with 124 genes overexpressed and 215 genes underexpressed in RA relative to OA.

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When observing for new biological pathways, investigators selected 13 clusters with DMER enrichment suitable for functional pathway analysis. Of the 13 clusters analyzed, 9 with active enhancer regions had predominant differences between RA and OA in the number H3K27ac. The other 4 clusters with active promoter regions had marked differences for H3K4me3 and H3K27ac.

The pathways that were enriched on the EpiSig were clusters involving inflammation, immune response matrix regulation, and cell migration, verifying the known disease mechanisms of RA. Importantly, RA-specific pathways such as role of osteoblasts, osteoclasts, and chondrocytes in OA and role of macrophages, fibroblasts, and endothelial cells in RA were significant and enriched in active enhancer regions, distinguishing RA from OA.

Other significant pathways included signaling via phospholipase C, p53, integrins, and protein kinase A.

One interesting finding was that Huntington disease signaling was also enriched, signifying a potential association between RA and Huntington disease. Upon examination of this pathway, investigators found the Huntingtin-interacting protein-1 (HIP1) to appear in many key locations. The HIP1 protein, expressed on fibroblast-like synoviocytes (FLS), was then tested to see if it correlated with cartilage and joint damage. When tested in vitro, HIP1 deficiency led to decreased RA FLS invasion close to 50%. This significant finding suggests that HIP1 may play a role in the pathogenesis of RA.

Although additional epigenomic research is warranted to explore potential pathways and targets for RA, the possibility remains for these studies to present new individualized drug treatments in the coming years.

“As genes involved are discovered, researchers can potentially identify new treatment options and even repurpose existing drugs, said Gary S. Firestein, MD, dean and associate vice chancellor of translational medicine at the University of California San Diego School of Medicine, and senior author of the study, in a news release.


Ai R, Laragione T, Hammaker D, et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun. 2018;9(1):1921. doi: 10.1038/s41467-018-04310-9.

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