Table10_Decoding mutational hotspots in human disease through the gene modules governing thymic regulatory T cells.xlsx

Computational strategies to extract meaningful biological information from multiomics data are in great demand for effective clinical use, particularly in complex immune-mediated disorders. Regulatory T cells (Tregs) are essential for immune homeostasis and self-tolerance, controlling inflammatory and autoimmune processes in many diseases with a multigenic basis. Here, we quantify the Transcription Factor (TF) differential occupancy landscape to uncover the Gene Regulatory Modules governing lineage-committed Tregs in the human thymus, and show that it can be used as a tool to prioritise variants in complex diseases. We combined RNA-seq and ATAC-seq and generated a matrix of differential TF binding to genes differentially expressed in Tregs, in contrast to their counterpart conventional CD4 single-positive thymocytes. The gene loci of both established and novel genetic interactions uncovered by the Gene Regulatory Modules were significantly enriched in rare variants carried by patients with common variable immunodeficiency, here used as a model of polygenic-based disease with severe inflammatory and autoimmune manifestations. The Gene Regulatory Modules controlling the Treg signature can, therefore, be a valuable resource for variant classification, and to uncover new therapeutic targets. Overall, our strategy can also be applied in other biological processes of interest to decipher mutational hotspots in individual genomes.

从多组学数据（multiomics data）中提取有生物学意义信息的计算策略，在高效临床应用领域需求迫切，尤其针对复杂免疫介导性疾病（immune-mediated disorders）。调节性T细胞（Regulatory T cells, Tregs）对免疫稳态与自身耐受至关重要，可调控多种多基因基础疾病中的炎症与自身免疫过程。本研究通过定量分析转录因子（Transcription Factor, TF）差异结合景观，以揭示人类胸腺中谱系定型调节性T细胞的基因调控模块（Gene Regulatory Modules, GRMs），并证实该模块可作为优先筛选复杂疾病致病变异的工具。本研究整合RNA测序（RNA-seq）与转座酶可及性测序（ATAC-seq）数据，构建了调节性T细胞相较于其对应群体——常规CD4单阳性胸腺细胞——中差异表达基因的TF差异结合矩阵。本研究通过基因调控模块揭示的已知与新型遗传互作的基因位点，显著富集于普通变异型免疫缺陷病（common variable immunodeficiency, CVID）患者携带的罕见变异中；本研究将普通变异型免疫缺陷病作为兼具重度炎症与自身免疫表现的多基因疾病模型。因此，调控调节性T细胞特征的基因调控模块，可作为致病变异分类与挖掘新型治疗靶点的宝贵资源。总体而言，本研究的计算策略还可推广至其他感兴趣的生物学过程，以解析个体基因组中的突变热点。