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 BarwinskaMahla 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, Blue Lake, Alexander Morales, Isaac Stillman, Stewart Lecker, Steve Bogen, Ashish Verma, Guanghao Yu, Insa Schmidt, Joel Henderson, Laurence Beck, Pranav Yadati, Sushrut Waikar, Afolarin A. Amodu, Shana Maikhor, Titlayo Ilori, Mia R. Colona, Astrid Weins, Gearoid McMahon, Nir Hacohen, Anna Greka, Jamie L. Marshall, Paul J. Hoover, Vidya S. Viswanathan, Dana Crawford, Mark Aulisio, William Bush, Yijiang Chen, Anant Madabhushi, Charles O’Malley, Crystal Gadegbeku, Dianna Sendrey, Emilio Poggio, John O’Toole, John Sedor, Jonathan Taliercio, Lakeshia Bush, Leal Herlitz, Ellen Palmer, Jane Nguyen, Kassandra Spates-Harden, Leslie Cooperman, Stacey Jolly, Carissa Vinovskis, Andrew Bomback, Jonathan Barasch, Krzysztof Kiryluk, Paul Appelbaum, Vivette D’Agati, Cecilia Berrouet, Karla Mehl, Maya Sabatello, Ning Shang, Olivia Balderes, Pietro A. Canetta, Satoru Kudose, Joana de Pinho Gonçalves, Lukasz Migas, Raf Van de Plas, Roy Lardenoije, Laura Barisoni, Helmut Rennke, Abraham Verdoes, Angela Sabo, Debora Lidia Gisch, James Williams, Katherine Kelly, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Pierre Dagher, Seth Winfree, Sharon Bledsoe, Stephanie Wofford, Tarek Ashkar (El-Achkar), Timothy Sutton, William Bowen, Austen Slade, Elizabeth Record, Yinghua Cheng, Yashvardhan Jain, Bruce Herr, Ellen Quardokus, Ashley Wang, Celia Pamela Corona Villalobos, Chirag Parikh, Mohamed Atta, Steven Menez, Yumeng Wen, Alan Xu, Lauren Bernard, Camille Johansen, Sarah Chen, Sylvia Rosas, Isabel Donohoe, Jennifer Sun, Richard Knight, Anna Shpigel, Jack Bebiak, John Saul, Joseph Ardayfio, Robert Koewler, Roy Pinkeney, Taneisha Campbell, Evren Azeloglu, Girish Nadkarni, John He, Joji Tokita, Kirk Campbell, Marissa Patel, Sean Lefferts, Srinivas Ravi Iyengar, Stephen Ward, Steven Coca, Cijang He, Yuguang Xiong, Pottumarthi Prasad, Brad Rovin, John P. Shapiro, Samir Parikh, Sethu M. Madhavan, Jessica Lukowski, Dusan Velickovic, Ljiljana Pasa-Tolic, George (Holt) Oliver, Olga Troyanskaya, Rachel Sealfon, Weiguang Mao, Aaron Wong, Ari Pollack, Yury Goltsev, Brandon Ginley, Brendon Lutnick, Garry Nolan, Kavya Anjani, Tariq Mukatash, Zoltan G. Laszik, Baltazar Campos, Bijin Thajudeen, David Beyda, Erika Bracamonte, Frank Brosius, Gregory Woodhead, Katherine Mendoza, Nicole Marquez, Raymond Scott, Rebecca Tsosie, Milda Saunders, Adele Rike, E. Steve Woodle, Paul J. Lee, Rita R. Alloway, Tiffany Shi, Elena Hsieh, Jessica Kendrick, Joshua Thurman, Julia Wrobel, Laura Pyle, Petter Bjornstad, Nicholas Lucarelli, Pinaki Sarder, Amada Renteria, Ana Ricardo, Anand Srivastava, Devona Redmond, Eunice Carmona-Powell, James Bui, James Lash, Monica Fox, Natalie Meza, Ron Gaba, Suman Setty, Tanika Kelly, Chrysta Lienczewski, Dawit Demeke, Edgar Otto, Heather Ascani, Jeff Hodgin, Jennifer Schaub, John Hartman, Laura Mariani, Markus Bitzer, Michael Rose, Nikki Bonevich, Ninive Conser, Phillip McCown, Rachel Dull, Rajasree Menon, Rebecca Reamy, Sean Eddy, Ul Balis, Victoria Blanc, Viji Nair, Yongqun Oliver He, Zachary Wright, Becky Steck, Jinghui Luo, Renee Frey, Alyson Coleman, Dorisann Henderson-Brown, Jerica Berge, Maria Luiza Caramori, Oyedele Adeyi, Patrick Nachman, Sami Safadi, Siobhan Flanagan, Sisi Ma, Susan Klett, Susan Wolf, Tasma Harindhanavudhi, Via Rao, Amy Mottl, Anne Froment, Evan Zeitler, Peter Bream, Sara Kelley, Matthew Rosengart, Michele Elder, Paul Palevsky, Raghavan Murugan, Daniel E. Hall, Filitsa Bender, James Winters, John A. Kellum, Matthew Gilliam, Mitchell Tublin, Roderick Tan, Guanshi Zhang, Kumar Sharma, Manjeri Venkatachalam, Allen Hendricks, Asra Kermani, Jose Torrealba, Miguel Vazquez, Nancy Wang, Qi Cai, Richard Tyler Miller, Shihong Ma, Susan Hedayati, Andrew Hoofnagle, Artit Wangperawong, Ashley Berglund, Ashveena L. Dighe, Bessie Young, Brandon Larson, Brooke Berry, Charles Alpers, Christine Limonte, Christy Stutzke, Glenda Roberts, Ian de Boer, Jaime Snyder, Jimmy Phuong, Jonas Carson, Kasra Rezaei, Katherine Tuttle, Keith Brown, Kristina Blank, Natalya Sarkisova, Nichole Jefferson, Robyn McClelland, Sean Mooney, Yunbi Nam, Adam Wilcox, Christopher Park, Frederick Dowd, Kayleen Williams, Stephanie M. Grewenow, Stephen Daniel, Stuart Shankland, Annapurna Pamreddy, Hongping Ye, Richard Montellano, Shweta Bansal, Anil Pillai, Dianbo Zhang, Harold Park, Jiten Patel, Kamalanathan Sambandam, Mujeeb Basit, Natasha Wen, Orson W. Moe, Robert D. Toto, Simon C. Lee, Kavya Sharman, Richard M. Caprioli, Agnes Fogo, Jamie Allen, Jeffrey Spraggins, Katerina Djambazova, Mark de Caestecker, Martin Dufresne, Melissa Farrow, Anitha Vijayan, Brittany Minor, Gerald Nwanne, Joseph Gaut, Kristine Conlon, Madhurima Kaushal, Sabine M. Diettman, Angela M. Victoria Castro, Dennis Moledina, Francis P. Wilson, Gilbert Moeckel, Lloyd Cantley, Melissa Shaw, Vijayakumar Kakade, Tanima Arora, Sanjay Jain, Michael Rauchman, Michael T. Eadon

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Article number433
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024
Externally publishedYes

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