Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan

Siqi Chen; Ruiyang Liu; Chia Kuei Mo; Michael C. Wendl; Andrew Houston; Preet Lal; Yanyan Zhao; Wagma Caravan; Andrew T. Shinkle; Atieh Abedin-Do; Nataly Naser Al Deen; Kazuhito Sato; Xiang Li; André Luiz N. Targino da Costa; Yize Li; Alla Karpova; John M. Herndon; Maxim N. Artyomov; Joshua B. Rubin; Sanjay Jain; Xue Li; Sheila A. Stewart; Li Ding; Feng Chen

doi:10.1038/s41588-025-02161-x

Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan

Siqi Chen, Ruiyang Liu, Chia Kuei Mo, Michael C. Wendl, Andrew Houston, Preet Lal, Yanyan Zhao, Wagma Caravan, Andrew T. Shinkle, Atieh Abedin-Do, Nataly Naser Al Deen, Kazuhito Sato, Xiang Li, André Luiz N. Targino da Costa, Yize Li, Alla Karpova, John M. Herndon, Maxim N. Artyomov, Joshua B. Rubin, Sanjay JainXue Li, Sheila A. Stewart, Li Ding, Feng Chen

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Abstract

There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.

Original language	English
Article number	1396
Pages (from-to)	1213-1227
Number of pages	15
Journal	Nature Genetics
Volume	57
Issue number	5
DOIs	https://doi.org/10.1038/s41588-025-02161-x
State	Published - May 2025

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Chen, S., Liu, R., Mo, C. K., Wendl, M. C., Houston, A., Lal, P., Zhao, Y., Caravan, W., Shinkle, A. T., Abedin-Do, A., Naser Al Deen, N., Sato, K., Li, X., Targino da Costa, A. L. N., Li, Y., Karpova, A., Herndon, J. M., Artyomov, M. N., Rubin, J. B., ... Chen, F. (2025). Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan. Nature Genetics, 57(5), 1213-1227. Article 1396. https://doi.org/10.1038/s41588-025-02161-x

@article{f625d6e4d39b4faba670b7725477a3fd,

title = "Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan",

abstract = "There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.",

author = "Siqi Chen and Ruiyang Liu and Mo, {Chia Kuei} and Wendl, {Michael C.} and Andrew Houston and Preet Lal and Yanyan Zhao and Wagma Caravan and Shinkle, {Andrew T.} and Atieh Abedin-Do and {Naser Al Deen}, Nataly and Kazuhito Sato and Xiang Li and {Targino da Costa}, {Andr{\'e} Luiz N.} and Yize Li and Alla Karpova and Herndon, {John M.} and Artyomov, {Maxim N.} and Rubin, {Joshua B.} and Sanjay Jain and Xue Li and Stewart, {Sheila A.} and Li Ding and Feng Chen",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = may,

doi = "10.1038/s41588-025-02161-x",

language = "English",

volume = "57",

pages = "1213--1227",

journal = "Nature Genetics",

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Chen, S, Liu, R, Mo, CK, Wendl, MC, Houston, A, Lal, P, Zhao, Y, Caravan, W, Shinkle, AT, Abedin-Do, A, Naser Al Deen, N, Sato, K, Li, X, Targino da Costa, ALN, Li, Y, Karpova, A, Herndon, JM, Artyomov, MN , Rubin, JB , Jain, S, Li, X, Stewart, SA , Ding, L & Chen, F 2025, 'Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan', Nature Genetics, vol. 57, no. 5, 1396, pp. 1213-1227. https://doi.org/10.1038/s41588-025-02161-x

TY - JOUR

T1 - Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan

AU - Chen, Siqi

AU - Liu, Ruiyang

AU - Mo, Chia Kuei

AU - Wendl, Michael C.

AU - Houston, Andrew

AU - Lal, Preet

AU - Zhao, Yanyan

AU - Caravan, Wagma

AU - Shinkle, Andrew T.

AU - Abedin-Do, Atieh

AU - Naser Al Deen, Nataly

AU - Sato, Kazuhito

AU - Li, Xiang

AU - Targino da Costa, André Luiz N.

AU - Li, Yize

AU - Karpova, Alla

AU - Herndon, John M.

AU - Artyomov, Maxim N.

AU - Rubin, Joshua B.

AU - Jain, Sanjay

AU - Li, Xue

AU - Stewart, Sheila A.

AU - Ding, Li

AU - Chen, Feng

PY - 2025/5

Y1 - 2025/5

N2 - There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.

AB - There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.

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SP - 1213

EP - 1227

JO - Nature Genetics

JF - Nature Genetics

IS - 5

M1 - 1396

ER -

Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan

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