Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic β Cell Identity and Function

Nathan Lawlor, Eladio J. Márquez, Peter Orchard, Narisu Narisu, Muhammad Saad Shamim, Asa Thibodeau, Arushi Varshney, Romy Kursawe, Michael R. Erdos, Matt Kanke, Huiya Gu, Evgenia Pak, Amalia Dutra, Sheikh Russell, Xingwang Li, Emaly Piecuch, Oscar Luo, Peter S. Chines, Christian Fuchbserger, NIH Intramural Sequencing Center, Praveen Sethupathy, Aviva Presser Aiden, Yijun Ruan, Erez Lieberman Aiden, Francis S. Collins, Duygu Ucar, Stephen C. J. Parker, Michael L. Stitzel.
Cell Reports. 2019-01-15;26(3):788-801.e6.
EndoC-βH1 is emerging as a critical human β cell model to study the genetic and environmental etiologies of β cell (dys)function and diabetes. Comprehensive knowledge of its molecular landscape is lacking, yet required, for effective use of this model. Here, we report chromosomal (spectral karyotyping), genetic (genotyping), epigenomic (ChIP-seq and ATAC-seq), chromatin interaction (Hi-C and Pol2 ChIA-PET), and transcriptomic (RNA-seq and miRNA-seq) maps of EndoC-βH1. Analyses of these maps define known (e.g., PDX1 and ISL1) and putative (e.g., PCSK1 and mir-375) β cell-specific transcriptional cis-regulatory networks and identify allelic effects on cis-regulatory element use. Importantly, comparison with maps generated in primary human islets and/or β cells indicates preservation of chromatin looping but also highlights chromosomal aberrations and fetal genomic signatures in EndoC-βH1. Together, these maps, and a web application we created for their exploration, provide important tools for the design of experiments to probe and manipulate the genetic programs governing β cell identity and (dys)function in diabetes.
Consortium data used in this publication