Systems Epigenetics, Otto-Warburg-Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Computational Modelling in Medicine, Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Mol Syst Biol. 2023 Nov 9;19(11):e11510. doi: 10.15252/msb.202211510. Epub 2023 Sep 21.
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.
在哺乳动物胚胎发育的早期阶段，女性的两条 X 染色体都有活性，直到通过 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 染色体剂量会影响细胞信号转导并损害分化。然而，其潜在机制仍知之甚少。为了剖析 X 染色体剂量对 mESCs 信号网络的影响，我们将系统的扰动实验与数学建模相结合。我们针对具有一条 X 染色体（XO）或两条 X 染色体（XX）的细胞，定量测定了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，为 XX 和 XO 细胞的信号网络构建模型。我们通过 GSK3 鉴定了 PI3K/AKT 通路中的一种新的负反馈。此外，单个活性 X 染色体的存在使 mESCs 对促进分化的激活素 A 信号更敏感，并导致 FGF 触发的 MAPK 通路中 RAF1 介导的负反馈更强。对这些促进分化的途径的不同反应可以解释雌性 mESCs 分化倾向受损的原因。
