Distinct Gene Regulatory Pathways for Human Innate Versus Adaptive Lymphoid Cells [ChIP-seq & ATAC-seq]

Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been studied extensively in model organisms, little is known about these “first responders” in humans, especially their lineage and functional kinships to cytokine-secreting T helper cell (Th) counterparts. Here, we report gene regulatory circuitries for four human ILC–Th counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells, but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell identity genes in each lineage, uncovering new modes of regulation for signature cytokines, novel molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILC–Th subsets. Molecular profiling of innate lymphoid and T helper cells subsets purified from tonsils and NK cells purified from peripheral blood using Assay for Transposase-Accessible Chromatin (ATAC) and chromatin immunoprecipitation (H3K4me3 and H3K27ac).

固有淋巴细胞（Innate lymphoid cells，ILCs）作为黏膜组织中的哨兵，可感知可溶性炎症介质的释放，通过分泌细胞因子快速传递危险信号，并作为组织稳态的守护者发挥功能。尽管科研人员已在模式生物中对ILCs展开了广泛研究，但对于人类体内的这类“第一道应答者”，我们的认知仍十分有限，尤其是它们与分泌细胞因子的辅助性T细胞（T helper cell，Th）同类之间的谱系及功能亲缘关系。本研究报道了四类源自黏膜环境的人类ILC与Th对应细胞的基因调控网络，研究显示，每一种ILC亚群均从Th及循环自然杀伤细胞（natural killer cells，NK）中分化为独立谱系，但与对应的Th同类共享调控功能极化的基因网络。超级增强子（super-enhancers）可界定各谱系中的细胞身份基因簇，同时揭示了标志性细胞因子的新型调控模式、可能赋予ILCs重要功能的新型分子，以及ILC-Th亚群内自身免疫病单核苷酸多态性（single nucleotide polymorphism，SNP）关联的潜在机制。本研究采用转座酶可及性染色质测序（Assay for Transposase-Accessible Chromatin，ATAC）与染色质免疫沉淀（chromatin immunoprecipitation，针对H3K4me3及H3K27ac两种组蛋白修饰）技术，对从扁桃体中纯化得到的固有淋巴细胞、辅助性T细胞亚群，以及从外周血中纯化得到的NK细胞开展了分子谱分析。