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

Arigela Harikumar, Patrick S.L. Lim, Malka Nissim-Rafinia, Jung Eun Park, Siu Kwan Sze, Eran Meshorer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 β-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 β-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 β-catenin in SET-regulated early differentiation and raise a hypothesis for SET function at the β-catenin-TCF regulatory axis.

Original languageAmerican English
Pages (from-to)1260-1274
Number of pages15
JournalStem Cell Reports
Volume15
Issue number6
DOIs
StatePublished - 8 Dec 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors

Keywords

  • Wnt
  • chromatin
  • differentiation
  • embryonic stem cells
  • epigenetics
  • p53
  • pluripotency
  • β-catenin

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