Russel, M. | Search bioRxiv

bioRxiv2025

Intestinal stem cell marker MEX3A regulates PPARγ expression with functional impact in colorectal carcinogenesis

RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of MEX3A in maintaining intestinal stem cell identity and epithelial renewal by repressing the PPAR{gamma} pathway. This work aimed to study MEX3A functional impact in colorectal cancer (CRC). MEX3A and PPAR{gamma} expression profiles were characterized in murine and human models. CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids (PDCTs) and MEX3A RNA targets identified through the HyperTRIBE technique. Apc+/fl;Mex3a+/- mice presented a significant reduction in tumor burden. Apc+/fl;Kras+/G12D;Mex3a+/-mice presented a reduced tumor area, while corresponding tumoroids exhibited reduced growth and enhanced differentiation potential mediated by PPAR{gamma} signalling. MEX3A overexpression (85% of human CRC cases) was inversely correlated with PPAR{gamma} downregulation (72% of cases). Accordingly, MEX3A-depleted PDCTs showed decreased LGR5 expression, accompanied by increased PPAR{gamma} expression and higher sensitivity to 5-Fluorouracil/Oxaliplatin (FOLFOX)-based chemotherapy. The HyperTRIBE results revealed a direct interaction between MEX3A and PPARG transcripts. STATEMENT OF SIGNIFICANCEThese results emphasize that MEX3A plays a crucial role in colorectal carcinogenesis, partially through regulation of the PPARG pathway, mediating tumour development and response to therapy, thus constituting a potential therapeutic target.

cancer biology↗

bioRxiv2024

Switch-like Gene Expression Modulates Disease Susceptibility

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.

bioinformatics↗