Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney
Abstract
Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.
Additional Information
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. The authors thank members of the McMahon laboratory for helpful comments on experimental design and members of the Kim laboratory for useful discussion on single-cell analyses. Work in A.P.M.'s laboratory is supported by a grant from the National Institutes of Health (R01 DK126925). A.L.M. acknowledges support from the National Institutes of Health (R35GM143019) and the National Science Foundation (DMS2045327). Author Contributions. APM conceived the study. Funding support was generated by APM, JK and LP. Data were collected by JL, KK and JG and analyzed by LX, JL, SYH, MR, FG and IBH in consultation with APM, ALM, JK and LP. LX, JL, ALM and APM wrote the manuscript incorporating comments from all participants. Data and Code Availability. RNA-seq data have been deposited at Gene Expression Omnibus and are publicly available as of the date of publication. All original code has been deposited on GitHub (https://github.com/LingyunXiong/Kidney_SexDiff). Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. The authors have declared no competing interest.Attached Files
Submitted - nihpp-2023.05.06.539585v2.pdf
Supplemental Material - media-1.pdf
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Additional details
- PMCID
- PMC10187285
- Eprint ID
- 122023
- Resolver ID
- CaltechAUTHORS:20230628-257103000.21
- NIH
- R01 DK126925-01
- NIH
- R35GM143019
- NSF
- DMS-2045327
- Created
-
2023-06-30Created from EPrint's datestamp field
- Updated
-
2023-06-30Created from EPrint's last_modified field
- Caltech groups
- Tianqiao and Chrissy Chen Institute for Neuroscience, Division of Biology and Biological Engineering
- Publication Status
- Submitted