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

doi:10.1016/j.celrep.2018.12.083

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

Cell Rep. 2019 Jan 15;26(3):788-801.e6. doi: 10.1016/j.celrep.2018.12.083.

Authors

Nathan Lawlor¹, Eladio J Márquez¹, Peter Orchard², Narisu Narisu³, Muhammad Saad Shamim⁴, Asa Thibodeau¹, Arushi Varshney⁵, Romy Kursawe¹, Michael R Erdos³, Matt Kanke⁶, Huiya Gu⁷, Evgenia Pak³, Amalia Dutra³, Sheikh Russell⁸, Xingwang Li¹, Emaly Piecuch⁹, Oscar Luo¹, Peter S Chines³, Christian Fuchbserger¹⁰; NIH Intramural Sequencing Center; Praveen Sethupathy⁶, Aviva Presser Aiden¹¹, Yijun Ruan¹, Erez Lieberman Aiden¹², Francis S Collins³, Duygu Ucar¹³, Stephen C J Parker¹⁴, Michael L Stitzel¹⁵

Affiliations

¹ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
² Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
³ National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁴ Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Computer Science, Department of Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA.
⁵ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
⁷ Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Computer Science, Department of Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA.
⁹ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT 06032, USA.
¹⁰ Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioengineering, Rice University, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Computer Science, Department of Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹³ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT 06032, USA; Institute for Systems Genomics, University of Connecticut, Farmington, CT 06032, USA.
¹⁴ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁵ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT 06032, USA; Institute for Systems Genomics, University of Connecticut, Farmington, CT 06032, USA. Electronic address: michael.stitzel@jax.org.

Abstract

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.

Keywords: (epi)genome; EndoC-βH1; Hi-C; Pol2 ChIA-PET; genetics; human pancreatic islets; karyotype; transcriptome; type 2 diabetes; β cell.

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

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