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 language | English (US) |
|---|---|
| Article number | 433 |
| Journal | Nature communications |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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In: Nature communications, Vol. 15, No. 1, 433, 12.2024.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - The chromatin landscape of healthy and injured cell types in the human kidney
AU - Gisch, Debora L.
AU - Brennan, Michelle
AU - Lake, Blue B.
AU - Basta, Jeannine
AU - Keller, Mark S.
AU - Melo Ferreira, Ricardo
AU - Akilesh, Shreeram
AU - Ghag, Reetika
AU - Lu, Charles
AU - Cheng, Ying Hua
AU - Collins, Kimberly S.
AU - Parikh, Samir V.
AU - Rovin, Brad H.
AU - Robbins, Lynn
AU - Stout, Lisa
AU - Conklin, Kimberly Y.
AU - Diep, Dinh
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AU - Knoten, Amanda
AU - Barwinska, Daria
AU - Asghari, Mahla
AU - Sabo, Angela R.
AU - Ferkowicz, Michael J.
AU - Sutton, Timothy A.
AU - Kelly, Katherine J.
AU - De Boer, Ian H.
AU - Rosas, Sylvia E.
AU - Kiryluk, Krzysztof
AU - Hodgin, Jeffrey B.
AU - Alakwaa, Fadhl
AU - Winfree, Seth
AU - Jefferson, Nichole
AU - Türkmen, Aydın
AU - Gaut, Joseph P.
AU - Gehlenborg, Nils
AU - Phillips, Carrie L.
AU - El-Achkar, Tarek M.
AU - Dagher, Pierre C.
AU - Hato, Takashi
AU - Zhang, Kun
AU - Himmelfarb, Jonathan
AU - Kretzler, Matthias
AU - Mollah, Shamim
AU - Lake, Blue
AU - Morales, Alexander
AU - Stillman, Isaac
AU - Lecker, Stewart
AU - Bogen, Steve
AU - Verma, Ashish
AU - Yu, Guanghao
AU - Schmidt, Insa
AU - Henderson, Joel
AU - Beck, Laurence
AU - Yadati, Pranav
AU - Waikar, Sushrut
AU - Amodu, Afolarin A.
AU - Maikhor, Shana
AU - Ilori, Titlayo
AU - Colona, Mia R.
AU - Weins, Astrid
AU - McMahon, Gearoid
AU - Hacohen, Nir
AU - Greka, Anna
AU - Marshall, Jamie L.
AU - Hoover, Paul J.
AU - Viswanathan, Vidya S.
AU - Crawford, Dana
AU - Aulisio, Mark
AU - Bush, William
AU - Chen, Yijiang
AU - Madabhushi, Anant
AU - O’Malley, Charles
AU - Gadegbeku, Crystal
AU - Sendrey, Dianna
AU - Poggio, Emilio
AU - O’Toole, John
AU - Sedor, John
AU - Taliercio, Jonathan
AU - Bush, Lakeshia
AU - Herlitz, Leal
AU - Palmer, Ellen
AU - Nguyen, Jane
AU - Spates-Harden, Kassandra
AU - Cooperman, Leslie
AU - Jolly, Stacey
AU - Vinovskis, Carissa
AU - Bomback, Andrew
AU - Barasch, Jonathan
AU - Kiryluk, Krzysztof
AU - Appelbaum, Paul
AU - D’Agati, Vivette
AU - Berrouet, Cecilia
AU - Mehl, Karla
AU - Sabatello, Maya
AU - Shang, Ning
AU - Balderes, Olivia
AU - Canetta, Pietro A.
AU - Kudose, Satoru
AU - de Pinho Gonçalves, Joana
AU - Migas, Lukasz
AU - Van de Plas, Raf
AU - Lardenoije, Roy
AU - Barisoni, Laura
AU - Rennke, Helmut
AU - Verdoes, Abraham
AU - Sabo, Angela
AU - Gisch, Debora Lidia
AU - Williams, James
AU - Kelly, Katherine
AU - Dunn, Kenneth
AU - Eadon, Michael
AU - Ferkowicz, Michael
AU - Dagher, Pierre
AU - Winfree, Seth
AU - Bledsoe, Sharon
AU - Wofford, Stephanie
AU - (El-Achkar), Tarek Ashkar
AU - Sutton, Timothy
AU - Bowen, William
AU - Slade, Austen
AU - Record, Elizabeth
AU - Cheng, Yinghua
AU - Jain, Yashvardhan
AU - Herr, Bruce
AU - Quardokus, Ellen
AU - Wang, Ashley
AU - Villalobos, Celia Pamela Corona
AU - Parikh, Chirag
AU - Atta, Mohamed
AU - Menez, Steven
AU - Wen, Yumeng
AU - Xu, Alan
AU - Bernard, Lauren
AU - Johansen, Camille
AU - Chen, Sarah
AU - Rosas, Sylvia
AU - Donohoe, Isabel
AU - Sun, Jennifer
AU - Knight, Richard
AU - Shpigel, Anna
AU - Bebiak, Jack
AU - Saul, John
AU - Ardayfio, Joseph
AU - Koewler, Robert
AU - Pinkeney, Roy
AU - Campbell, Taneisha
AU - Azeloglu, Evren
AU - Nadkarni, Girish
AU - He, John
AU - Tokita, Joji
AU - Campbell, Kirk
AU - Patel, Marissa
AU - Lefferts, Sean
AU - Iyengar, Srinivas Ravi
AU - Ward, Stephen
AU - Coca, Steven
AU - He, Cijang
AU - Xiong, Yuguang
AU - Prasad, Pottumarthi
AU - Rovin, Brad
AU - Shapiro, John P.
AU - Parikh, Samir
AU - Madhavan, Sethu M.
AU - Lukowski, Jessica
AU - Velickovic, Dusan
AU - Pasa-Tolic, Ljiljana
AU - Oliver, George (Holt)
AU - Troyanskaya, Olga
AU - Sealfon, Rachel
AU - Mao, Weiguang
AU - Wong, Aaron
AU - Pollack, Ari
AU - Goltsev, Yury
AU - Ginley, Brandon
AU - Lutnick, Brendon
AU - Nolan, Garry
AU - Anjani, Kavya
AU - Mukatash, Tariq
AU - Laszik, Zoltan G.
AU - Campos, Baltazar
AU - Thajudeen, Bijin
AU - Beyda, David
AU - Bracamonte, Erika
AU - Brosius, Frank
AU - Woodhead, Gregory
AU - Mendoza, Katherine
AU - Marquez, Nicole
AU - Scott, Raymond
AU - Tsosie, Rebecca
AU - Saunders, Milda
AU - Rike, Adele
AU - Woodle, E. Steve
AU - Lee, Paul J.
AU - Alloway, Rita R.
AU - Shi, Tiffany
AU - Hsieh, Elena
AU - Kendrick, Jessica
AU - Thurman, Joshua
AU - Wrobel, Julia
AU - Pyle, Laura
AU - Bjornstad, Petter
AU - Lucarelli, Nicholas
AU - Sarder, Pinaki
AU - Renteria, Amada
AU - Ricardo, Ana
AU - Srivastava, Anand
AU - Redmond, Devona
AU - Carmona-Powell, Eunice
AU - Bui, James
AU - Lash, James
AU - Fox, Monica
AU - Meza, Natalie
AU - Gaba, Ron
AU - Setty, Suman
AU - Kelly, Tanika
AU - Lienczewski, Chrysta
AU - Demeke, Dawit
AU - Otto, Edgar
AU - Ascani, Heather
AU - Hodgin, Jeff
AU - Schaub, Jennifer
AU - Hartman, John
AU - Mariani, Laura
AU - Bitzer, Markus
AU - Rose, Michael
AU - Bonevich, Nikki
AU - Conser, Ninive
AU - McCown, Phillip
AU - Dull, Rachel
AU - Menon, Rajasree
AU - Reamy, Rebecca
AU - Eddy, Sean
AU - Balis, Ul
AU - Blanc, Victoria
AU - Nair, Viji
AU - He, Yongqun Oliver
AU - Wright, Zachary
AU - Steck, Becky
AU - Luo, Jinghui
AU - Frey, Renee
AU - Coleman, Alyson
AU - Henderson-Brown, Dorisann
AU - Berge, Jerica
AU - Caramori, Maria Luiza
AU - Adeyi, Oyedele
AU - Nachman, Patrick
AU - Safadi, Sami
AU - Flanagan, Siobhan
AU - Ma, Sisi
AU - Klett, Susan
AU - Wolf, Susan
AU - Harindhanavudhi, Tasma
AU - Rao, Via
AU - Mottl, Amy
AU - Froment, Anne
AU - Zeitler, Evan
AU - Bream, Peter
AU - Kelley, Sara
AU - Rosengart, Matthew
AU - Elder, Michele
AU - Palevsky, Paul
AU - Murugan, Raghavan
AU - Hall, Daniel E.
AU - Bender, Filitsa
AU - Winters, James
AU - Kellum, John A.
AU - Gilliam, Matthew
AU - Tublin, Mitchell
AU - Tan, Roderick
AU - Zhang, Guanshi
AU - Sharma, Kumar
AU - Venkatachalam, Manjeri
AU - Hendricks, Allen
AU - Kermani, Asra
AU - Torrealba, Jose
AU - Vazquez, Miguel
AU - Wang, Nancy
AU - Cai, Qi
AU - Miller, Richard Tyler
AU - Ma, Shihong
AU - Hedayati, Susan
AU - Hoofnagle, Andrew
AU - Wangperawong, Artit
AU - Berglund, Ashley
AU - Dighe, Ashveena L.
AU - Young, Bessie
AU - Larson, Brandon
AU - Berry, Brooke
AU - Alpers, Charles
AU - Limonte, Christine
AU - Stutzke, Christy
AU - Roberts, Glenda
AU - de Boer, Ian
AU - Snyder, Jaime
AU - Phuong, Jimmy
AU - Carson, Jonas
AU - Rezaei, Kasra
AU - Tuttle, Katherine
AU - Brown, Keith
AU - Blank, Kristina
AU - Sarkisova, Natalya
AU - Jefferson, Nichole
AU - McClelland, Robyn
AU - Mooney, Sean
AU - Nam, Yunbi
AU - Wilcox, Adam
AU - Park, Christopher
AU - Dowd, Frederick
AU - Williams, Kayleen
AU - Grewenow, Stephanie M.
AU - Daniel, Stephen
AU - Shankland, Stuart
AU - Pamreddy, Annapurna
AU - Ye, Hongping
AU - Montellano, Richard
AU - Bansal, Shweta
AU - Pillai, Anil
AU - Zhang, Dianbo
AU - Park, Harold
AU - Patel, Jiten
AU - Sambandam, Kamalanathan
AU - Basit, Mujeeb
AU - Wen, Natasha
AU - Moe, Orson W.
AU - Toto, Robert D.
AU - Lee, Simon C.
AU - Sharman, Kavya
AU - Caprioli, Richard M.
AU - Fogo, Agnes
AU - Allen, Jamie
AU - Spraggins, Jeffrey
AU - Djambazova, Katerina
AU - de Caestecker, Mark
AU - Dufresne, Martin
AU - Farrow, Melissa
AU - Vijayan, Anitha
AU - Minor, Brittany
AU - Nwanne, Gerald
AU - Gaut, Joseph
AU - Conlon, Kristine
AU - Kaushal, Madhurima
AU - Diettman, Sabine M.
AU - Victoria Castro, Angela M.
AU - Moledina, Dennis
AU - Wilson, Francis P.
AU - Moeckel, Gilbert
AU - Cantley, Lloyd
AU - Shaw, Melissa
AU - Kakade, Vijayakumar
AU - Arora, Tanima
AU - Jain, Sanjay
AU - Rauchman, Michael
AU - Eadon, Michael T.
N1 - Publisher Copyright: © 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85181869068&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85181869068&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-44467-6
DO - 10.1038/s41467-023-44467-6
M3 - Article
C2 - 38199997
AN - SCOPUS:85181869068
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 433
ER -