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Journal Article Epublish 5 citations

PubMed: 40533442 DOI: 10.1038/s41467-025-60513-x

Switch-like gene expression modulates disease risk.

Nat Commun 16(1):5323

Authors: Alber Aqil, Yanyan Li, Zhiliang Wang, Saiful Islam, Madison Russell, Theodora Kunovac Kallak, Marie Saitou, Omer Gokcumen, Naoki Masuda

Affiliations

  • Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
  • Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA.
  • Institute for Artificial Intelligence and Data Science, State University of New York at Buffalo, Buffalo, NY, USA.
  • Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
  • Faculty of Biosciences, Norwegian University of Life Sciences, Aas, Norway.
  • Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
  • Department of Mathematics, State University of New York at Buffalo, Buffalo, NY, USA.
  • Institute for Artificial Intelligence and Data Science, State University of New York at Buffalo, Buffalo, NY, USA.

Abstract

While switch-like gene expression ("on" in some individuals and "off" in others) has been linked to biological variation and disease susceptibility, a systematic analysis across tissues is lacking. Here, we analyze genomes, transcriptomes, and methylomes from 943 individuals across 27 tissues, identifying 473 switch-like genes. The identified genes are enriched for associations with cancers and immune, metabolic, and skin diseases. Only 40 (8.5%) switch-like genes show genetically controlled switch-like expression in all tissues, i.e., universally switch-like expression. The rest show switch-like expression in specific tissues. Methylation analysis suggests that genetically driven epigenetic silencing explains the universally switch-like pattern, whereas hormone-driven epigenetic modification likely underlies the tissue-specific pattern. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, driven by tissue-specific master regulators. In the vagina, we identified seven concordantly switched-off genes linked to vaginal atrophy in females. Experimental analysis of vaginal tissues shows that low estrogen levels lead to decreased epithelial thickness and ALOX12 expression. We propose that switched-off driver genes in basal and parabasal epithelia suppress cell proliferation, leading to epithelial thinning and vaginal atrophy. Our findings underscore the implications of switch-like genes for diagnostic and personalized therapeutic applications.

MeSH

Genes, Atrophy, Tissues, Vagina, Gene Expression

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