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

IF 9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Systems Pub Date : 2023-09-20 Epub Date: 2023-08-25 DOI:10.1016/j.cels.2023.07.008
Teresa E Knudsen, William B Hamilton, Martin Proks, Maria Lykkegaard, Madeleine Linneberg-Agerholm, Alexander V Nielsen, Marta Perera, Luna Lynge Malzard, Ala Trusina, Joshua M Brickman
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Abstract

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.

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ESRRB的二分功能可以随着时间的推移整合信号,以平衡自我更新和分化。
转录因子的协同DNA结合整合了细胞环境,以支持发育过程中的细胞规范。天真的小鼠胚胎干细胞来源于早期发育,可以无限期地维持其多能干特性。在这里,我们询问与多能性相关的转录因子是否进化为直接支持这种状态,或者这种状态是否是从它们的组合作用中产生的。NANOG和ESRRB是共同结合DNA的关键多能性因子。我们发现,当两种因子都表达时,ESRRB支持多能性。然而,当NANOG不存在时,ESRRB支持具有胚胎样原始内胚层特性的细胞的双稳态培养,该特性辅助多能性。NANOG和ESRRB之间的化学计量允许对这种分化进行定量滴定,并且在二分ESRRB活性的计算机建模中表明,它保护了分化中的可塑性。因此,协同转录因子的协同活性可以改变其作用,以维持中间细胞身份,并允许永生干细胞的离体扩增。本文的透明同行评审过程记录包含在补充信息中。
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来源期刊
Cell Systems
Cell Systems Medicine-Pathology and Forensic Medicine
CiteScore
16.50
自引率
1.10%
发文量
84
审稿时长
42 days
期刊介绍: In 2015, Cell Systems was founded as a platform within Cell Press to showcase innovative research in systems biology. Our primary goal is to investigate complex biological phenomena that cannot be simply explained by basic mathematical principles. While the physical sciences have long successfully tackled such challenges, we have discovered that our most impactful publications often employ quantitative, inference-based methodologies borrowed from the fields of physics, engineering, mathematics, and computer science. We are committed to providing a home for elegant research that addresses fundamental questions in systems biology.
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