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EndoC-βH1 multi-genomic profiling defines gene regulatory programs governing 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: https://doi.org/10.1101/399139
Nathan Lawlor
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Eladio J. Márquez
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Peter Orchard
2Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA
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Narisu Narisu
3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Muhammad Saad Shamim
4Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
5Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
7Department of Computer Science, Department of Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA
8Department of Bioengineering, Rice University, Houston, TX 77030, USA
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Asa Thibodeau
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Arushi Varshney
9Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
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Romy Kursawe
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Michael R. Erdos
3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Matt Kanke
10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
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Huiya Gu
4Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Evgenia Pak
3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Amalia Dutra
3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Sheikh Russell
4Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
7Department of Computer Science, Department of Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA
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Xingwang Li
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Emaly Piecuch
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Oscar Luo
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Peter S. Chines
3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Christian Fuchbserger
11Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA
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Praveen Sethupathy
10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
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Aviva Presser Aiden
4Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
8Department of Bioengineering, Rice University, Houston, TX 77030, USA
12Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Yijun Ruan
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
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Erez Lieberman Aiden
4Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
7Department of Computer Science, Department of Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA
13Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
14BroadInstitute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA
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Francis S. Collins
3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Duygu Ucar
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
15Institute for Systems Genomics, University of Connecticut, Farmington, CT, 06032, USA
16Department of Genetics & Genome Sciences, University of Connecticut, Farmington, CT, 06032, USA
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Stephen C.J. Parker
2Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA
9Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
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Michael L. Stitzel
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
15Institute for Systems Genomics, University of Connecticut, Farmington, CT, 06032, USA
16Department of Genetics & Genome Sciences, University of Connecticut, Farmington, CT, 06032, USA
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  • For correspondence: michael.stitzel@jax.org
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SUMMARY

EndoC-βH1 is emerging as a critical human beta cell model to study the genetic and environmental etiologies of beta cell function, especially in the context of diabetes. Comprehensive knowledge of its molecular landscape is lacking yet required to fully take advantage of this model. 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 known (e.g., PDX1, ISL1) and putative (e.g., PCSK1, mir-375) beta cell-specific chromatin interactions and transcriptional cis-regulatory networks, and identify allelic effects on cis-regulatory element use and expression.

Importantly, comparative analyses with maps generated in primary human islets/beta cells indicate substantial preservation of chromatin looping, but also highlight chromosomal heterogeneity and fetal genomic signatures in EndoC-βH1. Together, these maps, and an interactive web application we have created for their exploration, provide important tools for the broad community in the design and success of experiments to probe and manipulate the genetic programs governing beta cell identity and (dys)function in diabetes.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 23, 2018.
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EndoC-βH1 multi-genomic profiling defines gene regulatory programs governing 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
bioRxiv 399139; doi: https://doi.org/10.1101/399139
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EndoC-βH1 multi-genomic profiling defines gene regulatory programs governing 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
bioRxiv 399139; doi: https://doi.org/10.1101/399139

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