Epithelial stem cells self-renew although sustaining multipotency, but the dependence of stem cell properties DNA Methyltransferase signaling inhibitor on servicing of your epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 retain properties of the two sternness and epithelial-mesenchymal transition (EMT). Right here, we present that MAP3K4 controls the action on the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to sustain the epithelial phenotype. Combined reduction of MAP3K4/CBP exercise represses expression of epithelial genes FGFR and brings about IS cells to undergo EMT when sustaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken with each other, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer.