EndoC-BH1 multiomic profiling defines gene regulatory programs intrinsic to human beta cell identity and function

EndoC-BH1 is emerging as a critical human beta cell model to study the genetic and environmental etiologies of normal islet function as well as beta cell failure in diabetes. However, comprehensive knowledge of its (epi)genomic landscape has been lacking. Here, we report extensive chromosomal (spectral karyotyping), genetic (genotyping), epigenetic (ChIP-seq, ATAC-seq), chromatin interaction (Hi-C, Pol2 ChIA-PET), and transcriptomic (RNA-seq, miRNA-seq) maps of this cell model. Integrated analyses of these maps define beta cell-specific chromosome territories and transcriptional cis-regulatory programs and identify allelic effects on cis-regulatory element use and expression. Importantly, comparative analyses with maps generated in human islets/beta cells indicate substantial preservation of cis-regulatory element use and chromatin looping. Together, these maps and an interactive web application we have created for their exploration are important tools for the design and completion of experiments to probe and manipulate the genetic programs governing beta cell identity and (dys)function in diabetes.

EndoC-BH1 现已成为研究正常胰岛功能及糖尿病中β细胞衰竭的遗传与环境病因的关键人类β细胞模型。然而，学界此前始终缺乏对其（表观）基因组全貌的全面认知。本研究系统性构建了该细胞模型的多组学全景图谱，涵盖染色体（光谱核型分析）、遗传（基因分型）、表观遗传（染色质免疫沉淀测序（ChIP-seq）、转座酶可及性测序（ATAC-seq））、染色质互作（高通量染色体构象捕获（Hi-C）、RNA聚合酶II染色质免疫沉淀配对末端标签测序（Pol2 ChIA-PET））以及转录组（RNA测序（RNA-seq）、微小RNA测序（miRNA-seq））层面的深度表征数据。对上述图谱的整合分析揭示了β细胞特异性染色体领地与转录顺式调控程序，并明确了等位基因对顺式调控元件使用及基因表达的调控效应。尤为重要的是，将本研究图谱与人类胰岛/β细胞中生成的同类图谱进行比较分析后发现，顺式调控元件的使用模式与染色质环结构存在高度保守性。综上，本研究构建的各类图谱及我们开发的用于该图谱探索的交互式网页应用程序，将为设计与开展实验以探究、调控糖尿病中维持β细胞身份及其功能异常的遗传程序提供重要工具。