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RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

View ORCID ProfileJohn T. Walker, View ORCID ProfileDiane C. Saunders, View ORCID ProfileVivek Rai, Chunhua Dai, View ORCID ProfilePeter Orchard, View ORCID ProfileAlexander L. Hopkirk, View ORCID ProfileConrad V. Reihsmann, View ORCID ProfileYicheng Tao, Simin Fan, View ORCID ProfileShristi Shrestha, View ORCID ProfileArushi Varshney, View ORCID ProfileJordan J. Wright, View ORCID ProfileYasminye D. Pettway, View ORCID ProfileChrista Ventresca, Samir Agarwala, Radhika Aramandla, Greg Poffenberger, Regina Jenkins, View ORCID ProfileNathaniel J. Hart, Dale L. Greiner, View ORCID ProfileLeonard D. Shultz, View ORCID ProfileRita Bottino, Human Pancreas Analysis Program, View ORCID ProfileJie Liu, View ORCID ProfileStephen C.J. Parker, View ORCID ProfileAlvin C. Powers, View ORCID ProfileMarcela Brissova
doi: https://doi.org/10.1101/2021.12.16.466282
John T. Walker
1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
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Diane C. Saunders
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Vivek Rai
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Chunhua Dai
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Peter Orchard
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Alexander L. Hopkirk
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Conrad V. Reihsmann
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Yicheng Tao
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Simin Fan
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Shristi Shrestha
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Arushi Varshney
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Jordan J. Wright
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Yasminye D. Pettway
1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
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Christa Ventresca
4Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Samir Agarwala
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Radhika Aramandla
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Greg Poffenberger
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Regina Jenkins
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Nathaniel J. Hart
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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Dale L. Greiner
5Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA
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Leonard D. Shultz
6The Jackson Laboratory, Bar Harbor, Maine, 04609, USA
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Rita Bottino
7Imagine Pharma, Devon, Pennsylvania, 19333, USA
8Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, 15212, USA
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9Human Islet Research Network (RRID:SCR_014393)
Jie Liu
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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Stephen C.J. Parker
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA
4Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA
10Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, 48109, USA
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  • For correspondence: marcela.brissova@vanderbilt.edu al.powers@vumc.org scjp@umich.edu
Alvin C. Powers
1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
11VA Tennessee Valley Healthcare System, Nashville, Tennessee, 37212, USA
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  • For correspondence: marcela.brissova@vanderbilt.edu al.powers@vumc.org scjp@umich.edu
Marcela Brissova
2Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA
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  • For correspondence: marcela.brissova@vanderbilt.edu al.powers@vumc.org scjp@umich.edu
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SUMMARY

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells1–3. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging4–6. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

Competing Interest Statement

The authors have declared no competing interest.

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Posted December 17, 2021.
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RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes
John T. Walker, Diane C. Saunders, Vivek Rai, Chunhua Dai, Peter Orchard, Alexander L. Hopkirk, Conrad V. Reihsmann, Yicheng Tao, Simin Fan, Shristi Shrestha, Arushi Varshney, Jordan J. Wright, Yasminye D. Pettway, Christa Ventresca, Samir Agarwala, Radhika Aramandla, Greg Poffenberger, Regina Jenkins, Nathaniel J. Hart, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Human Pancreas Analysis Program, Jie Liu, Stephen C.J. Parker, Alvin C. Powers, Marcela Brissova
bioRxiv 2021.12.16.466282; doi: https://doi.org/10.1101/2021.12.16.466282
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RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes
John T. Walker, Diane C. Saunders, Vivek Rai, Chunhua Dai, Peter Orchard, Alexander L. Hopkirk, Conrad V. Reihsmann, Yicheng Tao, Simin Fan, Shristi Shrestha, Arushi Varshney, Jordan J. Wright, Yasminye D. Pettway, Christa Ventresca, Samir Agarwala, Radhika Aramandla, Greg Poffenberger, Regina Jenkins, Nathaniel J. Hart, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Human Pancreas Analysis Program, Jie Liu, Stephen C.J. Parker, Alvin C. Powers, Marcela Brissova
bioRxiv 2021.12.16.466282; doi: https://doi.org/10.1101/2021.12.16.466282

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