Sex differences are widespread across human development, physiological processes, and diseases. Importantly, in addition to characterizing sex differences, elucidating their regulatory mechanisms, such as modulation by androgens, has major implications for clinical translation of the diseases prevalent in one sex over the other. However, a molecular and cellular profile of sex differences and their modulation by androgens is still lacking.
In a study published in Nature, the team led by Prof. GAO Dong and Prof. CHEN Luonan from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Prof. BAI Fan from Peking University and Prof. YU Chen from Shenzhen Bay Laboratory comprehensively explores the role of androgens in shaping sex differences at the molecular and cellular levels.
The researchers developed a detailed single-cell transcriptomic map from 17 different tissues of the mouse (Mus musculus), allowing for an in-depth analysis of sex differences and how androgens influence these differences through specific molecular pathways, cell types, and their implications for sex-biased diseases.
They pinpointed the genes (defined as AASB-DEGs), the expressions of which are sex-biased and influenced by androgens in various cell types across the 17 tissues examined. These genes, including Egfr, Fos, and Il33, are highlighted as potential targets for precision medicine by targeting the androgen pathway.
The study also detailed how androgens affect the prevalence of certain cell types across sexes in various tissues, notably within immune cell populations. A key finding was the identification of group 2 innate lymphoid cells (ILC2s), which play a role in inflammation and enhancing PD-1 blockade therapy. Interestingly, ILC2s exhibited the highest expression levels of androgen receptor (Ar) among the major immune cell types. The presence of these cells was notably affected by androgen levels, suggesting a mechanism by which androgens could influence immune responses and disease susceptibility.
Additionally, by integrating their findings with data from the UK Biobank, the team discovered that the most significant risk genes for sex-biased diseases were enriched in major histocompatibility complex (MHC) genes, some of which showed sex differences or were androgen-responsive. Cross-species analyses based on this atlas also identified the associations between cell types and sex-biased diseases.
Overall, this comprehensive study sheds light on the intricate ways in which androgens contribute to sex differences at cellular and molecular levels, offering promising avenues for developing targeted therapies for sex-biased diseases by modulating the androgen pathway.
Contact: dong.gao@sibcb.ac.cn
Reference: https://www.nature.com/articles/s41586-024-07291-6
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