A bipartite function of ESRRB can integrate signaling over time to balance self-renewal and differentiation
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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A bipartite function of ESRRB can integrate signaling over time to balance self-renewal and differentiation. / Knudsen, Teresa E.; Hamilton, William B.; Proks, Martin; Lykkegaard, Maria; Linneberg-Agerholm, Madeleine; Nielsen, Alexander V.; Perera, Marta; Malzard, Luna Lynge; Trusina, Ala; Brickman, Joshua M.
I: Cell Systems, Bind 14, Nr. 9, 2023, s. 788-805.e8.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 368253671