Modeling unveils sex differences of signaling networks in mouse embryonic stem cells.

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular Systems Biology Pub Date : 2023-11-09 Epub Date: 2023-09-21 DOI:10.15252/msb.202211510
Zeba Sultana, Mathurin Dorel, Bertram Klinger, Anja Sieber, Ilona Dunkel, Nils Blüthgen, Edda G Schulz
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引用次数: 0

Abstract

For a short period during early development of mammalian embryos, both X chromosomes in females are active, before dosage compensation is ensured through X-chromosome inactivation. In female mouse embryonic stem cells (mESCs), which carry two active X chromosomes, increased X-dosage affects cell signaling and impairs differentiation. The underlying mechanisms, however, remain poorly understood. To dissect X-dosage effects on the signaling network in mESCs, we combine systematic perturbation experiments with mathematical modeling. We quantify the response to a variety of inhibitors and growth factors for cells with one (XO) or two X chromosomes (XX). We then build models of the signaling networks in XX and XO cells through a semi-quantitative modeling approach based on modular response analysis. We identify a novel negative feedback in the PI3K/AKT pathway through GSK3. Moreover, the presence of a single active X makes mESCs more sensitive to the differentiation-promoting Activin A signal and leads to a stronger RAF1-mediated negative feedback in the FGF-triggered MAPK pathway. The differential response to these differentiation-promoting pathways can explain the impaired differentiation propensity of female mESCs.

模型揭示了小鼠胚胎干细胞中信号网络的性别差异。
在哺乳动物胚胎早期发育的短时间内,雌性的两条X染色体都是活跃的,然后通过X染色体失活来确保剂量补偿。在携带两条活性X染色体的雌性小鼠胚胎干细胞(mESCs)中,增加的X剂量会影响细胞信号传导并损害分化。然而,人们对其根本机制仍知之甚少。为了剖析X剂量对mESCs信号网络的影响,我们将系统扰动实验与数学建模相结合。我们量化了具有一条(XO)或两条X染色体(XX)的细胞对各种抑制剂和生长因子的反应。然后,我们通过基于模块化响应分析的半定量建模方法,建立XX和XO细胞中信号网络的模型。我们通过GSK3在PI3K/AKT通路中发现了一种新的负反馈。此外,单一活性X的存在使mESCs对促分化激活素a信号更敏感,并导致FGF触发的MAPK通路中更强的RAF1介导的负反馈。对这些分化促进途径的差异反应可以解释女性mESCs分化倾向受损的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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