Journal Article

Switch-like gene expression modulates disease risk

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

2025

Overview

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. While switch-like 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 switch-like genes are enriched for associations with cancers and immune, metabolic, and skin diseases. Only 40 (8.5%) switch-like genes show genetically hardwired on-versus-off expression in all tissues analyzed, i.e., universally switch-like expression. The remaining switch-like genes show on versus off expression only in specific tissues. Methylation analysis suggests that genetically driven epigenetic silencing explains the universal pattern, whereas hormone-driven epigenetic modification may underlie tissue-specific switch-like gene expression. 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. Experimental analysis of vaginal tissues shows that low estrogen levels lead to a decreased epithelial thickness and ALOX12 expression. We propose a model wherein 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/1 / 38/39 / 45 / 631/114/2404 / 631/208/199 / 692/499 / 82/51 / Atrophy / Biological variation / Cancer / Cell growth / Cell proliferation / Customization / DNA Methylation / Epigenesis, Genetic / Epigenetics / Epithelium / Estrogens / Estrogens - metabolism / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Genes / Genetic Predisposition to Disease / Genomes / Health risks / Humanities and Social Sciences / Humans / Male / Metabolism / Methylation / multidisciplinary / Organ Specificity - genetics / Science / Science (multidisciplinary) / Skin diseases / Therapeutic applications / Thickness / Thinning / Tissues / Transcriptome / Transcriptomes / Vagina / Vagina - metabolism / Vagina - pathology