Multiomics dissection of molecular regulatory mechanisms underlying autoimmune-associated noncoding SNPs

Abstract

More than 90% of autoimmune-associated variants are located in noncoding regions, leading to challenges in deciphering the underlying causal roles of functional variants and genes and biological mechanisms. Therefore, to reduce the gap between traditional genetic findings and mechanistic understanding of disease etiologies and clinical drug development, it is important to translate systematically the regulatory mechanisms underlying noncoding variants. Here, we prioritized functional noncoding SNPs with regulatory gene targets associated with 19 autoimmune diseases by incorporating hundreds of immune cell–specific multiomics data. The prioritized SNPs are associated with transcription factor (TF) binding, histone modification, or chromatin accessibility, indicating their allele-specific regulatory roles. Their target genes are significantly enriched in immunologically related pathways and other known immunologically related functions. We found that 90.1% of target genes are regulated by distal SNPs involving several TFs (e.g., the DNA-binding protein CCCTC-binding factor [CTCF]), suggesting the importance of long-range chromatin interaction in autoimmune diseases. Moreover, we predicted potential drug targets for autoimmune diseases, including 2 genes ( NFKB1 and SH2B3 ) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. Taken together, these findings may provide useful information for future experimental follow-up and drug applications on autoimmune diseases.

Integration of genetic and epigenetic data pinpoints autoimmune specific remodelling of enhancer landscape in CD4+ T cells

“…Enhancers are traditionally often linked to their nearest genes using proximity based methods, even though it is known that they can regulate their target genes over large genomic distances 82 , and autoimmune associated SNPs in non-coding regions are often affecting distal genes. 83 Our eGRNs can be used to identify distal enhancer-target gene links that would be missed using more conventional proximity based methods. As an example, we identified a distal enhancer linked to CTLA4 (chr2:203930706-203942262, with a distance of 60052 bp), that was also linked to ICOS (TSS, 0 bps) and CD28 (222190 bp).…”

Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci

“…In line with the critical roles of enhancers in the orchestration of gene expression in and outside of insulated chromatin domains [topologically associating domains (TADs); Fanucchi and Mhlanga, 2017], nucleotide variants and disruptions affecting enhancers, and potentially the transcription of eRNAs and lncRNAs generated from these regions, have been implicated in various diseases. This ranges from autoimmune diseases to mental disorders and cancer (Farh et al, 2015;Javierre et al, 2016;Teppo et al, 2016;Ren et al, 2017;Hauberg et al, 2019;Isoda et al, 2019;Lewis et al, 2019;Chen et al, 2020b;Yamagata et al, 2020). Thus, beyond lncRNAs encoded within coding gene regions or seemingly empty genomic space, genetic variation in transcribed regulatory DNA units, such as enhancers, contributes to human diseases.…”

Variant to Gene Mapping to Discover New Targets for Immune Tolerance

“…A separate study combined the SNPs associated with 19 autoimmune diseases with cell-specific multi-omics approaches to develop an epigenetic weighted scoring method to evaluate the functionality of all noncoding autoimmune SNPs. The analysis also suggested long-range chromatin interactions between functional SNPs and distal target genes, highlighting the unique regulatory roles of noncoding SNPs associated with autoimmune diseases ( 80 ).…”