TY - JOUR
T1 - Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution
AU - Muto, Yoshiharu
AU - Yoshimura, Yasuhiro
AU - Wu, Haojia
AU - Chang-Panesso, Monica
AU - Ledru, Nicolas
AU - Woodward, Owen M.
AU - Outeda, Patricia
AU - Cheng, Tao
AU - Mahjoub, Moe
AU - Watnick, Terry J.
AU - Humphreys, Benjamin
N1 - Publisher Copyright:
© 2024 the Author(s). Published by PNAS.
PY - 2024/10/22
Y1 - 2024/10/22
N2 - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late time-points, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single-nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late time-points, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single-nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
KW - mouse model
KW - multiomics
KW - PKD1
KW - polycystic kidney disease
KW - single cell analysis
UR - http://www.scopus.com/inward/record.url?scp=85206503585&partnerID=8YFLogxK
U2 - 10.1073/pnas.2410830121
DO - 10.1073/pnas.2410830121
M3 - Article
C2 - 39405347
AN - SCOPUS:85206503585
SN - 0027-8424
VL - 121
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
M1 - e2410830121
ER -