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

著者: 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 W. 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, the Kidney Precision Medicine Project (KPMP), Blue B. Lake, Alexander Morales, Isaac E. Stillman, Stewart H. Lecker, Steve Bogen, Ashish Verma, Guanghao Yu, Insa M. Schmidt, Joel Henderson, Laurence H. Beck, Pranav Yadati, Sushrut S. Waikar, Afolarin Amodu, Shana Maikhor, Titlayo Ilori, Mia R. Colona, Astrid Weins, Gearoid M. McMahon, Nir Hacohen, Anna Greka, Jamie L. Marshall, Paul Hoover, Vidya Sankar Viswanathan, Dana C. Crawford, Mark P. Aulisio, William S. Bush, Yijiang Chen, Anant Madabhushi, Charles M. O’Malley, Crystal A. Gadegbeku, Dianna Sendrey, Emilio D. Poggio, John O’Toole, John R. Sedor, Jonathan J. Taliercio, Lakeshia Bush, Leal Herlitz, Ellen L. Palmer, Jane Nguyen, Kassandra Spates-Harden, Leslie Cooperman, Stacey E. Jolly, Carissa Vinovskis, Andrew S. Bomback, Jonathan Barasch, Krzysztof Kiryluk, Paul S. Appelbaum, Vivette D. D’Agati, Cecilia Berrouet, Karla Mehl, Maya Sabatello, Ning Shang, Olivia Balderes, Pietro A. Canetta, Satoru Kudose, Joana P. Gonçalves, Lukasz G. Migas, Raf Van de Plas, Roy Lardenoije, Laura Barisoni, Helmut G. Rennke, Abraham Verdoes, Angela R. Sabo, Debora L. Gisch, James C. Williams, Katherine J. Kelly, Kenneth W. Dunn, Michael T. Eadon, Michael J. Ferkowicz, Pierre C. Dagher, Seth Winfree, Sharon B. Bledsoe, Stephanie Wofford, Timothy A. Sutton, William S. Bowen, Austen Slade, Elizabeth Record, Ying‐Hua Cheng, Yashvardhan Jain, Bruce W. Herr, Ellen M. Quardokus, Ashley Wang, Celia P. Corona‐Villalobos, Chirag R. Parikh, Mohamed G. Atta, Steven Menez, Yumeng Wen, Alan Xu, Lauren Bernard, Camille Johansen, Sarah Chen, Sylvia E. Rosas, Isabel Donohoe, Jennifer K. Sun, Richard A. Knight, Anna Shpigel, Jack Bebiak, John Saul, Joseph Ardayfio, Robert Koewler, Roy Pinkeney, Taneisha Campbell, Evren U. Azeloglu, Girish N. Nadkarni, John Cijiang He, Joji Tokita, Kirk N. Campbell, Marissa Patel, Sean Lefferts, Srinivas Ravi Iyengar, Stephen A. Ward, Steven G. Coca, Cijang He, Yuguang Xiong, Pottumarthi Prasad, Brad H. Rovin, John P. Shapiro, Samir V. Parikh, Sethu M. Madhavan, Jessica Lukowski, Dušan Veličković, Ljiljana Paša‐Tolić, George Oliver, Olga G. Troyanskaya, Rachel Sealfon, Weiguang Mao, Aaron K. Wong, Ari H. Pollack, Yury Goltsev, Brandon Ginley, Brendon Lutnick, Garry P. Nolan, Kavya Anjani, Tariq Mukatash, Zoltán Lászik, Baltazar Campos, Bijin Thajudeen, David H. Beyda, Erika Bracamonte, Frank C. Brosius, Gregory Woodhead, Katherine Mendoza, Nicole Marquez, Raymond Scott, Rebecca Tsosie, Milda R. Saunders, Adele Rike, E. Steve Woodle, Paul J. Lee, Rita R. Alloway, Tiffany Shi, Elena W.Y. Hsieh, Jessica Kendrick, Joshua M. Thurman, Julia Wrobel, Laura Pyle, Petter Bjornstad, Nicholas Lucarelli, Pinaki Sarder, Amada Renteria, Ana C. Ricardo, Anand Srivastava, D. Eugene Redmond, Eunice Carmona-Powell, James T. Bui, James P. Lash, Monica Fox, Natalie Meza, Ron C. Gaba, Suman Setty, Tanika N. Kelly, Chrysta Lienczewski, Dawit Demeke, Edgar A. Otto, Heather Ascani, Jeff Hodgin, Jennifer A. Schaub, John R. Hartman, Laura Mariani, Markus Bitzer, Michael Rose, Nikki Bonevich, Ninive C. Conser, Phillip J. McCown, Rachel Dull, Rajasree Menon, Rebecca Reamy, Sean Eddy, Ul Balis, Victoria M. Blanc, Viji Nair, Yongqun He, Zachary Wright, Becky Steck, Jinghui Luo, Renee Frey, Alyson Coleman, Dorisann Henderson-Brown, Jerica M. Berge, Maria Luiza Caramori, Oyedele Adeyi, Patrick H. Nachman, Sami Safadi, Siobhan Flanagan, Sisi Ma, Susan Klett, Susan M. Wolf, Tasma Harindhanavudhi, Via Rao, Amy K. Mottl, Anne Froment, Evan Zeitler, Peter R. Bream, Sara Kelley, Matthew R. Rosengart, Michele Elder, Paul M. Palevsky, Raghavan Murugan, Daniel E. Hall, Filitsa Bender, James Winters, John A. Kellum, Matthew Gilliam, Mitchell Tublin, Roderick J. Tan, Guanshi Zhang, Kumar Sharma, Manjeri A. Venkatachalam, Allen R. Hendricks, Asra Kermani, José Torrealba, Miguel A. Vazquez, Nancy Wang, Qi Cai, R. Tyler Miller, Shihong Ma, S. Susan Hedayati, Andrew N. Hoofnagle, Artit Wangperawong, Ashley Berglund, Ashveena Dighe, Bessie A. Young, Brandon Larson, Brooke Berry, Charles E. Alpers, Christine P. Limonte, Christy Stutzke, Glenda V. Roberts, Ian H. de Boer, Jaime Snyder, Jimmy Phuong, Jonas Carson, Kasra A. Rezaei, Katherine R. Tuttle, Keith Brown, Kristina N. Blank, Natalya Sarkisova, Nichole Jefferson, Robyn L. McClelland, Sean D. Mooney, Yunbi Nam, Adam Wilcox, Chris Park, Frederick Dowd, Kayleen Williams, Stephanie M. Grewenow, Stephen Daniel, Stuart J. Shankland, Annapurna Pamreddy, Hongping Ye, Richard Montellano, Shweta Bansal, Anil K. Pillai, Dianbo Zhang, Harold S. Park, Jiten Patel, Kamalanathan K. Sambandam, Mujeeb Basit, Natasha Wen, Orson W. Moe, Robert D. Toto, Simon J. Craddock Lee, Kavya Sharman, Richard M. Caprioli, Agnes B. Fogo, Jamie Allen, Jeffrey M. Spraggins, Katerina Djambazova, Mark de Caestecker, Martin Dufresne, Melissa A. Farrow, Anitha Vijayan, Brittany Minor, Gerald Nwanne, Joseph P. Gaut, Kristine Conlon, Madhurima Kaushal, Sabine M. Diettman, Angela M. Victoria Castro, Dennis G. Moledina, F. Perry Wilson, Gilbert Moeckel, Lloyd Cantley, Melissa Shaw, Vijayakumar R. Kakade, Tanima Arora, Sanjay Jain, Michael Rauchman, Michael T. Eadon - Nature Communications 2024 被引用: 39

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.