FOXO4-SP6 axis controls surface epithelium commitment by mediating epigenomic remodeling [RNA]
Proper development of surface epithelium (SE) is a requisite for the normal development and function of ectodermal appendages; however, the molecular mechanisms underlying SE commitment remain largely unexplored. Here, we developed a KRT8 reporter system and utilized it to identify FOXO4 and SP6 as novel, essential regulators governing SE commitment. We found that the FOXO4-SP6 axis governs SE fate and its abrogation markedly impedes SE fate determination. Mechanistically, FOXO4 regulates SE initiation by shaping the SE chromatin accessibility landscape and regulating the deposition of H3K4me3. SP6, as a novel effector of FOXO4, activated SE-specific genes through modulating the H3K27ac deposition across their super enhancers. Our work highlights the regulatory function of the FOXO4-SP6 axis in SE development, contributing to an improved understanding of SE fate decisions and providing a research foundation for the therapeutic application of ectodermal dysplasia. Overall design: To illustrate the function of FOXO4 and SP6 in regulating SE differentiation, we knocked down FOXO4 and SP6 in human embryonic stem cells (hESCs) by shRNAs, and then performed RNA-seq to obtain data from 4 different cells at two time points: the SE initiation stage in D3 and the maturation stage in D7.  Comparative gene expression analysis was conducted on the RNA-seq data from differentiated hESCs and their knockdown derivatives (shFOXO4 and shSP6).