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

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.