The chromatin landscape of healthy and injured cell types in the human kidney

Debora L. Gisch, Michelle Brennan, Blue B. Lake, Jeannine Basta, Mark S. Keller, Ricardo Melo Ferreira, Shreeram Akilesh, Reetika Ghag, Charles Lu, Ying-Hua Cheng, Kimberly S. Collins, Samir V. Parikh, Brad H. Rovin, Lynn Robbins, Lisa Stout, Kimberly Y. Conklin, Dinh Diep, Bo Zhang, Amanda Knoten, Daria Barwinska, Mahla Asghari, Angela R. Sabo, Michael J. Ferkowicz, Timothy A. Sutton, Katherine J. Kelly, Ian H. De Boer, Sylvia E. Rosas, Krzysztof Kiryluk, Jeffrey B. Hodgin, Fadhl Alakwaa, Seth Winfree, Nichole Jefferson, Aydın Türkmen, Joseph P. Gaut, Nils Gehlenborg, Carrie L. Phillips, Tarek M. El-Achkar, Pierre C. Dagher, Takashi Hato, Kun Zhang, Jonathan Himmelfarb, Matthias Kretzler, Shamim Mollah, Sanjay Jain (), Michael Rauchman () and Michael T. Eadon ()
Additional contact information
Debora L. Gisch: Indiana University School of Medicine
Michelle Brennan: Saint Louis University
Blue B. Lake: Department of Bioengineering, University of California, San Diego
Jeannine Basta: Washington University in Saint Louis
Mark S. Keller: Harvard Medical School
Ricardo Melo Ferreira: Indiana University School of Medicine
Shreeram Akilesh: University of Washington –
Reetika Ghag: Washington University in Saint Louis
Charles Lu: Washington University in Saint Louis
Ying-Hua Cheng: Indiana University School of Medicine
Kimberly S. Collins: Indiana University School of Medicine
Samir V. Parikh: Ohio State University Wexner Medical Center
Brad H. Rovin: Ohio State University Wexner Medical Center
Lynn Robbins: St. Louis Veteran Affairs Medical Center
Lisa Stout: Washington University in Saint Louis
Kimberly Y. Conklin: Department of Bioengineering, University of California, San Diego
Dinh Diep: Department of Bioengineering, University of California, San Diego
Bo Zhang: Washington University in Saint Louis
Amanda Knoten: Washington University in Saint Louis
Daria Barwinska: Indiana University School of Medicine
Mahla Asghari: Indiana University School of Medicine
Angela R. Sabo: Indiana University School of Medicine
Michael J. Ferkowicz: Indiana University School of Medicine
Timothy A. Sutton: Indiana University School of Medicine
Katherine J. Kelly: Indiana University School of Medicine
Ian H. De Boer: University of Washington –
Sylvia E. Rosas: Joslin Diabetes Center, Harvard Medical School
Krzysztof Kiryluk: Columbia University
Jeffrey B. Hodgin: University of Michigan
Fadhl Alakwaa: University of Michigan
Seth Winfree: University of Nebraska Medical Center
Nichole Jefferson: Kidney Precision Medicine Project Community Engagement Committee
Aydın Türkmen: Istanbul School of Medicine, Division of Nephrology
Joseph P. Gaut: Department of Bioengineering, University of California, San Diego
Nils Gehlenborg: Harvard Medical School
Carrie L. Phillips: Indiana University School of Medicine
Tarek M. El-Achkar: Indiana University School of Medicine
Pierre C. Dagher: Indiana University School of Medicine
Takashi Hato: Indiana University School of Medicine
Kun Zhang: Department of Bioengineering, University of California, San Diego
Jonathan Himmelfarb: University of Washington –
Matthias Kretzler: University of Michigan
Shamim Mollah: Washington University in Saint Louis
Sanjay Jain: Washington University in Saint Louis
Michael Rauchman: Washington University in Saint Louis
Michael T. Eadon: Indiana University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney’s active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

Date: 2024
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DOI: 10.1038/s41467-023-44467-6

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