MAP3K4 Kinase Activity Controls Chromatin Remodelers for Transitions Between Epithelial and Mesenchymal Phenotypes in Trophoblast Stem Cells [RNA-Seq]

MAP3K4 is a serine/threonine kinase that regulates epithelial to mesenchymal transition (EMT). Trophoblast stem (TS) cells lacking MAP3K4 kinase activity (TSKI4 cells) are in an intermediate state of EMT, having reduced epithelial and increased mesenchymal marker expression. Reduced epithelial gene expression in TSKI4 cells was due to loss of H2BK5 promoter acetylation catalyzed by the histone acetyltransferase CBP. Herein, we show that MAP3K4 also regulates the ubiquitination and degradation of the deacetylase HDAC6. Due to the loss of MAP3K4 kinase activity, TSKI4 cells have elevated HDAC6 expression and activity. Knockdown of HDAC6 in TSKI4 cells restores epithelial features, defining HDAC6 as a key regulator of EMT controlled by MAP3K4. HDAC6 promotes EMT by directly deacetylating H2BK5 on promoters of tight junction genes claudin6 and occludin, inhibiting their expression. Thus, MAP3K4 is a master regulator that coordinates chromatin modifiers, CBP and HDAC6, to regulate the transition between epithelial and mesenchymal states.