Embryonic Stem Cell Differentiation Is Regulated by SET through Interactions with p53 and ?-Catenin.

ABSTRACT: The multifunctional histone chaperone, SET, is essential for embryonic development in the mouse. Previously, we identified SET as a factor that is rapidly downregulated during embryonic stem cell (ESC) differentiation, suggesting a possible role in the maintenance of pluripotency. Here, we explore SET's function in early differentiation. Using immunoprecipitation coupled with protein quantitation by LC-MS/MS, we uncover factors and complexes, including P53 and ?-catenin, by which SET regulates lineage specification. Knockdown for P53 in SET-knockout (KO) ESCs partially rescues lineage marker misregulation during differentiation. Paradoxically, SET-KO ESCs show increased expression of several Wnt target genes despite reduced levels of active ?-catenin. Further analysis of RNA sequencing datasets hints at a co-regulatory relationship between SET and TCF proteins, terminal effectors of Wnt signaling. Overall, we discover a role for both P53 and ?-catenin in SET-regulated early differentiation and raise a hypothesis for SET function at the ?-catenin-TCF regulatory axis.

SUBMITTER: Harikumar A 

PROVIDER: S-EPMC7724474 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature