TY - JOUR
T1 - A balanced Oct4 interactome is crucial for maintaining pluripotency
AU - Han, Dong
AU - Wu, Guangming
AU - Chen, Rui
AU - Drexler, Hannes C.A.
AU - MacCarthy, Caitlin M.
AU - Kim, Kee Pyo
AU - Adachi, Kenjiro
AU - Gerovska, Daniela
AU - Mavrommatis, Lampros
AU - Bedzhov, Ivan
AU - Araúzo-Bravo, Marcos J.
AU - Schöler, Hans R.
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2022/2
Y1 - 2022/2
N2 - Oct4 collaborates primarily with other transcriptional factors or coregulators to maintain pluripotency. However, how Oct4 exerts its function is still unclear. Here, we show that the Oct4 linker interface mediates competing yet balanced Oct4 protein interactions that are crucial for maintaining pluripotency. Oct4 linker mutant embryonic stem cells (ESCs) show decreased expression of self-renewal genes and increased expression of differentiation genes, resulting in impaired ESC self-renewal and early embryonic development. The linker mutation interrupts the balanced Oct4 interactome. In mutant ESCs, the interaction between Oct4 and Klf5 is decreased. In contrast, interactions between Oct4 and Cbx1, Ctr9, and Cdc73 are increased, disrupting the epigenetic state of ESCs. Control of the expression level of Klf5, Cbx1, or Cdc73 rebalances the Oct4 interactome and rescues the pluripotency of linker mutant ESCs, indicating that such factors interact with Oct4 competitively. Thus, we provide previously unidentified molecular insights into how Oct4 maintains pluripotency.
AB - Oct4 collaborates primarily with other transcriptional factors or coregulators to maintain pluripotency. However, how Oct4 exerts its function is still unclear. Here, we show that the Oct4 linker interface mediates competing yet balanced Oct4 protein interactions that are crucial for maintaining pluripotency. Oct4 linker mutant embryonic stem cells (ESCs) show decreased expression of self-renewal genes and increased expression of differentiation genes, resulting in impaired ESC self-renewal and early embryonic development. The linker mutation interrupts the balanced Oct4 interactome. In mutant ESCs, the interaction between Oct4 and Klf5 is decreased. In contrast, interactions between Oct4 and Cbx1, Ctr9, and Cdc73 are increased, disrupting the epigenetic state of ESCs. Control of the expression level of Klf5, Cbx1, or Cdc73 rebalances the Oct4 interactome and rescues the pluripotency of linker mutant ESCs, indicating that such factors interact with Oct4 competitively. Thus, we provide previously unidentified molecular insights into how Oct4 maintains pluripotency.
UR - http://www.scopus.com/inward/record.url?scp=85124777292&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abe4375
DO - 10.1126/sciadv.abe4375
M3 - Article
C2 - 35171666
AN - SCOPUS:85124777292
SN - 2375-2548
VL - 8
JO - Science advances
JF - Science advances
IS - 7
M1 - eabe4375
ER -