475 High resolution chromatin loops associate with gene targets for psoriasis susceptibility regions

Abstract

There are over 80 psoriasis-associated loci identified, with a majority playing regulatory roles; however, their gene targets are yet to be identified. Chromatin loops play an important role in gene regulation, and can be detected by chromosome conformation capture techniques like Hi-C. In this study, we deep sequenced Hi-C libraries (∼1 billion reads/reaction) to generate nine PBMC-derived subsets from 2 individuals (∼50,000 cells each): 4 unstimulated CD3+CD45RO+ memory T cells (CD4+CLA-, CD4+CLA+, CD8+CLA-, CD8+CLA+); the same 4 subsets after 24 hours of CD3/CD28 stimulation of CD1c- cells (primarily T cells); and mDC. Using a 5k-10k contact map resolution, we identified 13,186 ± 2,857 Hi-C loops per library, ranging from 30 to 1,980 kb long, using Mustache. Notably, we found that ∼50% of the identified loops have at least one end overlapping a transcription start site, providing a unique resource for mapping long-range promoter interactions in immunocytes. We identified 27 ± 6 loops per library that linked to promoters and whose loop ends could also be mapped to known psoriasis signals, defined by the 95% credible intervals generated from a recent transethnic GWAS (HGG Adv 2022). Of 47 target genes involved in such loops, we found 8 previously suggested gene targets for psoriasis: ANXA6, ELMO1, ETS1, FASLG, MBD2, IFI44, PTGER4 and STARD6. Among them, ANXA6, ETS1, FASLG and IFI44 were present only in T cells, while the rest presented in both T cells and mDC. We further revealed other psoriasis gene candidates including KAT5, NHLRC3/PROSER1, and SUCO, which were linked to known psoriasis signals through loops in multiple Hi-C libraries for both individuals and in both T cells and mDC. This study provides complementary support for known psoriasis-related genes at the level of 3D genome structure, and nominates other genes of interest for future studies.