Trancriptomic and epigenetic analyses of mouse organoids expressing BrafV600E mutation [BiSulfite-seq]
收藏资源简介：
Abnormal promoter DNA hypermethylation arises early during tumorigenesis and yet its role in cancer initiation has remained underexplored. An important scenario for examining this is, BRAFV600E-mutant colon adenocarcinomas (COAD) which most often arise in the proximal colon and harbor extensive, abnormal gene promoter CpG-island methylation or the methylator phenotype (CIMP). How CIMP and BRAF-mutations specifically interact for COAD initiation has remained unclear. Using mouse colon-derived organoids, we show promoter hypermethylation spontaneously arises in wild type cells mimicking âaging likeâ phenotype. The silenced genes sufficiently activate the Wnt pathway, causing a stemâlike state and profound differentiation block. This phenotype renders long-term cultured organoids to be rapidly susceptible to transformation by BRAFV600E with features of typical right-sided COAD. Our studies tightly link epigenetic abnormalities, suggested to arise with aging, to intestinal cell fate changes and define an âepi-driverâ role for multiple abnormally silenced genes that predispose to BRAFV600E-driven colon tumorigenesis.
