Switch-like Gene Expression Modulates Disease Susceptibility

TL;DR

Switch-like gene expression patterns across tissues influence disease susceptibility, with some genes universally active and others tissue-specific, impacting conditions like gastric cancer and vaginal atrophy.

Contribution

The study systematically identifies switch-like genes across 27 tissues and links them to disease mechanisms, including hormonal regulation and epithelial thinning.

Findings

Only 3.1% of switch-like genes are active across all tissues, with five explained by genomic structural variants.

Tissue-specific switch-like genes are regulated by master regulators like hormones and are linked to diseases such as gastric cancer and vaginal atrophy.

Low estrogen levels reduce epithelial thickness and ALOX12 gene expression, contributing to vaginal atrophy.

Abstract

A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes. We found that only 31 (3.1%) of these genes exhibit switch-like behavior across all tissues. These universally switch-like genes appear to be genetically driven, with large exonic genomic structural variants explaining five (~18%) of them. The remaining switch-like genes exhibit tissue-specific expression patterns. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, likely under the influence of tissue-specific master regulators, including hormonal signals. Among our most significant findings, we identified hundreds of concordantly switched-off genes in the stomach and vagina that are linked to gastric cancer (41-fold, p<10−4) and vaginal atrophy (44-fold, p<10−4), respectively. Experimental analysis of vaginal tissues revealed that low systemic levels of estrogen lead to a significant reduction in both the epithelial thickness and the expression of the switch-like gene ALOX12. We propose a model wherein the switching off of driver genes in basal and parabasal epithelium suppresses cell proliferation therein, leading to epithelial thinning and, therefore, vaginal atrophy. Our findings underscore the significant biomedical implications of switch-like gene expression and lay the groundwork for potential diagnostic and therapeutic applications.

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