Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney
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1.
California Institute of Technology
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2.
University of Southern California
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 sequencing (RNA-seq) data demonstrated that 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, whereas 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, disease, and metabolic linkage of sexually dimorphic gene activity.
Copyright and License
© 2023 Elsevier.
Acknowledgement
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. We thank Dr. Ron Korstanje for orientating us to, and sharing data from, his groups analysis of multiple organs in a diversity outbred cross. 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).
Contributions
A.P.M. conceived the study. Funding support was generated by A.P.M., J.K., and L.P. Data were collected by J.L., K.K., and J.-J.G. and analyzed by L.X., J.L., S.Y.H., M.R., Z.M., F.G., and I.B.H. in consultation with A.P.M., A.L.M., J.K., and L.P. L.X., J.L., and A.P.M. wrote the manuscript incorporating comments from all participants.
Data Availability
- Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
- All original code has been deposited on GitHub (Zenodo archive: https://doi.org/10.5281/zenodo.8208547).
- RNA-seq data have been deposited at Gene Expression Omnibus and are publicly available as of the date of publication. Accession numbers are listed in the key resources table.
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Additional details
- PMCID
- PMC10873092
- National Institutes of Health
- R01 DK126925
- National Institutes of Health
- R35GM143019
- National Science Foundation
- DMS-2045327)
- Caltech groups
- Division of Biology and Biological Engineering
- Publication Status
- Published