TY - JOUR

T1 - A bipartite function of ESRRB can integrate signaling over time to balance self-renewal and differentiation

AU - Knudsen, Teresa E.

AU - Hamilton, William B.

AU - Proks, Martin

AU - Lykkegaard, Maria

AU - Linneberg-Agerholm, Madeleine

AU - Nielsen, Alexander V.

AU - Perera, Marta

AU - Malzard, Luna Lynge

AU - Trusina, Ala

AU - Brickman, Joshua M.

N1 - Publisher Copyright: © 2023

PY - 2023

Y1 - 2023

N2 - Cooperative DNA binding of transcription factors (TFs) integrates the cellular context to support cell specification during development. Naive mouse embryonic stem cells are derived from early development and can sustain their pluripotent identity indefinitely. Here, we ask whether TFs associated with pluripotency evolved to directly support this state or if the state emerges from their combinatorial action. NANOG and ESRRB are key pluripotency factors that co-bind DNA. We find that when both factors are expressed, ESRRB supports pluripotency. However, when NANOG is absent, ESRRB supports a bistable culture of cells with an embryo-like primitive endoderm identity ancillary to pluripotency. The stoichiometry between NANOG and ESRRB allows quantitative titration of this differentiation, and in silico modeling of bipartite ESRRB activity suggests it safeguards plasticity in differentiation. Thus, the concerted activity of cooperative TFs can transform their effect to sustain intermediate cell identities and allow ex vivo expansion of immortal stem cells. A record of this paper's transparent peer review process is included in the supplemental information.

AB - Cooperative DNA binding of transcription factors (TFs) integrates the cellular context to support cell specification during development. Naive mouse embryonic stem cells are derived from early development and can sustain their pluripotent identity indefinitely. Here, we ask whether TFs associated with pluripotency evolved to directly support this state or if the state emerges from their combinatorial action. NANOG and ESRRB are key pluripotency factors that co-bind DNA. We find that when both factors are expressed, ESRRB supports pluripotency. However, when NANOG is absent, ESRRB supports a bistable culture of cells with an embryo-like primitive endoderm identity ancillary to pluripotency. The stoichiometry between NANOG and ESRRB allows quantitative titration of this differentiation, and in silico modeling of bipartite ESRRB activity suggests it safeguards plasticity in differentiation. Thus, the concerted activity of cooperative TFs can transform their effect to sustain intermediate cell identities and allow ex vivo expansion of immortal stem cells. A record of this paper's transparent peer review process is included in the supplemental information.

KW - cooperativity

KW - ESCs

KW - plasticity

KW - pluripotency

KW - pre-implantation development

KW - primitive endoderm

KW - regulative development

KW - self-renewal

KW - transcription

U2 - 10.1016/j.cels.2023.07.008

DO - 10.1016/j.cels.2023.07.008

M3 - Journal article

C2 - 37633265

AN - SCOPUS:85171383010

VL - 14

SP - 788-805.e8

JO - Cell Systems

JF - Cell Systems

SN - 2405-4712

IS - 9

ER -