High resolution Hi-C map defines regulatory mechanism for atopic dermatitis associated signals

Summary: Three-dimensional (3D) genome architecture modulates gene regulation by altering DNA-DNA interactions, frequently linking regulatory elements to promoters. We aim to investigate how 3D genome reorganization of atopic dermatitis (AD) skin underlies gene dysregulation. We perform Hi-C experiments on paired lesional and non-lesional skin samples from 7 AD patients, utilizing ~1.8 billion reads per condition to achieve a resolution of 1,750bp. We identify 10,414 lesional and 13,171 non-lesional differential abundant loops (DALs) overlapping gene promoters. Multi-omics integration reveals that >60% of DALs link to promoters of skin expressed genes, and >75% of them also coincide with open chromatin regions defined by single nucleus multiome data. Notably, 9.6% of lesional DALs link to promoters of upregulated differentially expressed genes (DEGs), exceeding the 7.9% expected outcome. Single-cell RNA-seq integration indicates lesional DALs linked to upregulated DEGs are more enriched in T cells (3.48% vs 0.59%) and myeloid cells (6.47% vs 0.30%), but less in fibroblasts (4.14% vs 9.76%), compared to non-lesional DALs linked to downregulated DEGs. Furthermore, our recent GWAS suggests that 43.3% of AD associated loci are found in the DALs. Among the loci we highlight three which overlap with lesional DALs encompassing up-regulated genes (<i>SOCS1</i>, <i>IL6R</i>, <i>TRAF3</i>), and one with down-regulated DEG <i>BACH2 </i>(FC = 0.53, p-adjust < 0.001) associated with 5 non-lesional DALs spanning across 500kb in chromosome 6. These DALs, located within open chromatin regions, narrow down the pool of potential causal variants from 580 significant variants to 34 within the four loci, 27 of which are also eQTL for the connected genes. Our study thus reveals 3D chromatin reorganization in AD skin that correlates with transcriptional and immunological changes providing mechanistic insights into disease biology. Ruiwen Zhou¹, Haihan Zhang¹, Tony Lam², Rachael Bogle¹, Bridget Riley-Gillis², Elizabeth Asque², Sujana Ghosh², Tiffani Morin², Matthew Patrick¹, Robert Bissonnette³, Johann E. Gudjonsson¹, Lam C. Tsoi¹, Kathleen Smith² 1. University of Michigan, Ann Arbor, MI, United States. 2. AbbVie Inc, North Chicago, IL, United States. 3. Innovaderm Research, Montreal, QC, Canada. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics