Sex differences orchestrated by androgens at single-cell resolution

Fei Li; Xudong Xing; Qiqi Jin; Xiang-Ming Wang; Pengfei Dai; Ming Han; Huili Shi; Ze Zhang; Xianlong Shao; Yunyi Peng; Yiqin Zhu; Jiayi Xu; Dan Li; Yu Chen; Wei Wu; Qiao Wang; Chen Yu; Luonan Chen; Fan Bai; Dong Gao

doi:10.1038/s41586-024-07291-6

Sex differences orchestrated by androgens at single-cell resolution

Nature. 2024 May;629(8010):193-200. doi: 10.1038/s41586-024-07291-6. Epub 2024 Apr 10.

Authors

Fei Li^#¹, Xudong Xing^#², Qiqi Jin^#^{1

3

4}, Xiang-Ming Wang^#², Pengfei Dai^#^{1

3}, Ming Han^#^{1

3}, Huili Shi^{1

3}, Ze Zhang⁵, Xianlong Shao^{1

3}, Yunyi Peng^{1

3}, Yiqin Zhu¹, Jiayi Xu⁶, Dan Li⁷, Yu Chen⁷, Wei Wu⁸, Qiao Wang⁸, Chen Yu⁹, Luonan Chen^{10

11

12}, Fan Bai¹³, Dong Gao^{14

15}

Affiliations

¹ Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
² Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences, Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁵ Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
⁶ Shanghai Normal University, Shanghai, China.
⁷ Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁹ Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. yu@szbl.ac.cn.
¹⁰ Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. lnchen@sibcb.ac.cn.
¹¹ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. lnchen@sibcb.ac.cn.
¹² Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. lnchen@sibcb.ac.cn.
¹³ Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences, Beijing Advanced Innovation Center for Genomics (ICG), School of Life Sciences, Peking University, Beijing, China. fbai@pku.edu.cn.
¹⁴ Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China. dong.gao@sibcb.ac.cn.
¹⁵ Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China. dong.gao@sibcb.ac.cn.

^# Contributed equally.

PMID: 38600383
DOI: 10.1038/s41586-024-07291-6

Abstract

Sex differences in mammalian complex traits are prevalent and are intimately associated with androgens^1-7. However, a molecular and cellular profile of sex differences and their modulation by androgens is still lacking. Here we constructed a high-dimensional single-cell transcriptomic atlas comprising over 2.3 million cells from 17 tissues in Mus musculus and explored the effects of sex and androgens on the molecular programs and cellular populations. In particular, we found that sex-biased immune gene expression and immune cell populations, such as group 2 innate lymphoid cells, were modulated by androgens. Integration with the UK Biobank dataset revealed potential cellular targets and risk gene enrichment in antigen presentation for sex-biased diseases. This study lays the groundwork for understanding the sex differences orchestrated by androgens and provides important evidence for targeting the androgen pathway as a broad therapeutic strategy for sex-biased diseases.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Androgens* / metabolism
Androgens* / pharmacology
Animals
Antigen Presentation / drug effects
Antigen Presentation / genetics
Cells* / drug effects
Cells* / immunology
Cells* / metabolism
Female
Humans
Immunity, Innate
Lymphocytes / cytology
Lymphocytes / drug effects
Lymphocytes / immunology
Lymphocytes / metabolism
Male
Mice
Mice, Inbred C57BL
Sex Characteristics*
Single-Cell Analysis*
Transcriptome* / drug effects
Transcriptome* / genetics
UK Biobank

Substances

Androgens