13 - Analysis of Chromatin Data Supports A Role For Monocytes in Mediating Genetic Risk for Juvenile Idiopathic Arthritis

Friday, April 22, 2022

6:15 PM – 8:45 PM US MT

Poster Number: 13
Publication Number: 13.110

Elizabeth A. Crinzi, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, BUFFALO, NY, United States; Emma K. Haley, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States; James N. Jarvis, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, NY, United States

Presenting Author(s)

Jim N. Jarvis, MD

Professor of Pediatrics
Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo
Buffalo, New York, United States

Background: : Multiple genetic rik loci have been identified for juvenile idiopathic arthritis (JIA). However, the cells and cellular functions impacted by these variants remain unknown. We have shown that JIA risk loci are highly enriched in neutrophils for evidence of functional enhancers, but whether there are other innate immune cells that might be impacted by SNPs on JIA risk haplotypes is unknown.

Objective: To survey the chromatin architecture surrounding 36 JIA risk haplotypes in CD14+ monocytes to gather evidence that genetic risk for JIA impinges on innate immune functions, and to identify potential target genes of regulatory elements on JIA risk haplotypes.

Design/Methods: We queried publicly available H3K27ac/H3K4me1 ChIP-seq data in CD14+ monocytes to determine whether the JIA risk haplotypes are enriched (compared to genome background) for enhancers. We also queried existing monocyte/macrophage Global Run On-sequencing ( GROseq) data, a functional readout of active enhancers and performed similar enrichment analyses. . We next defined the topologically associated domains (TADs) encompassing the risk haplotypes that harbor the enhancers of interest using publicly available Hi-C data in THP-1 cells and CTCF ChiPseq data in human monocytes. We then completed ontological analysis of gene targets located within these TADs.

Results: We found significant enrichment for enhancer associated H3K4me1/H3K27ac on 22 JIA risk haplotypes in CD14+ monocytes as compared to random regions of the genome (p=0.00021 and p=0.022). Eleven and sixteen JIA haplotypes were also enriched for monocyte and macrophage GROseq peaks, respectively (p=0.04385 and p=0.00004). Using 3D chromatin and RNAseq data, we identified 524 expressed genes within the TADs that encompass these enhancers. Ontological analysis of these target genes showed significant enrichment for multiple disease-relevant immune functions, including MHC class II receptor activity, chemokine and cytokine binding, and IL-6 receptor binding.Conclusion(s): Chromatin and functional (GROseq) data support the idea that innate immunity is impacted by SNPs on JIA genetic risk haplotypes. RNAseq data and 3D features that surround the risk haplotypes reveal a large number of immunologically relevant genes that may be impacted by causal SNPs.