EndoC-ßH1 multiomic profiling defines gene regulatory programs intrinsic to human ß cell identity and function

EndoC-ßH1 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-βH1已成为研究正常胰岛功能及糖尿病中β细胞功能衰竭的遗传与环境病因的关键人类β细胞模型。然而，此前学界对其(表观)基因组图谱的全面认知仍存在空白。本研究报道了该细胞模型的多维度组学图谱：涵盖染色体层面的光谱核型分析（spectral karyotyping）、遗传层面的基因分型（genotyping）、表观遗传层面的染色质免疫共沉淀测序（ChIP-seq）、转座酶可及性测序（ATAC-seq），染色质相互作用层面的Hi-C、RNA聚合酶II染色质相互作用分析配对末端标签测序（Pol2 ChIA-PET），以及转录组层面的RNA测序（RNA-seq）、小分子RNA测序（miRNA-seq）。对上述图谱的整合分析明确了β细胞特异性的染色体疆域（chromosome territories）与转录顺式调控程序，并揭示了等位基因效应（allelic effects）对顺式调控元件（cis-regulatory element）使用及基因表达的调控作用。尤为重要的是，通过与人类胰岛/β细胞中生成的图谱进行比较分析，本研究发现顺式调控元件使用模式与染色质环（chromatin looping）结构存在显著保守性。综上，本研究生成的全部图谱，以及我们开发的用于图谱探索的交互式网页应用程序，共同构成了重要的研究工具，可用于设计并开展实验，以探究和操控调控糖尿病中β细胞身份与功能异常的遗传程序。