Dynamic map illuminates Hippo-cMyc module crosstalk driving cardiomyocyte proliferation.

IF 3.7 2区生物学 Q1 DEVELOPMENTAL BIOLOGY

Development Pub Date : 2025-02-15 Epub Date: 2025-02-17 DOI:10.1242/dev.204397

Bryana N Harris, Laura A Woo, R Noah Perry, Alexia M Wallace, Mete Civelek, Matthew J Wolf, Jeffrey J Saucerman

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Abstract

Numerous regulators of cardiomyocyte (CM) proliferation have been identified, yet how they coordinate during cardiac development or regeneration is poorly understood. Here, we developed a computational model of the CM proliferation regulatory network to obtain key regulators and systems-level understanding. The model defines five modules (DNA replication, mitosis, cytokinesis, growth factor, Hippo pathway) and integrates them into a network of 72 nodes and 88 reactions that correctly predicts 74 of 81 (91.35%) independent experiments from the literature. The model predicts that in response to YAP activation, the Hippo module crosstalks to the growth factor module via PI3K and cMyc to drive cell cycle activity. This predicted YAP-cMyc axis is validated experimentally in rat CMs and further supported by YAP-stimulated cMyc open chromatin and mRNA in mouse hearts. This validated computational model predicts how individual regulators and modules coordinate to control CM proliferation.

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动态图阐明hipo - cmyc模块串扰驱动心肌细胞增殖。

已经确定了许多心肌细胞（CM）增殖的调节因子，但它们在心脏发育或再生过程中如何协调尚不清楚。在这里，我们开发了一个CM增殖调控网络的计算模型，以获得关键的调控因子和系统级的理解。该模型定义了五个模块（DNA复制、有丝分裂、细胞质分裂、生长因子、Hippo通路），并将它们整合到一个由72个节点和88个反应组成的网络中，该网络正确预测了78个独立实验中的73个（93.6%）。该模型预测，在响应YAP激活时，Hippo模块通过PI3K和cMyc串串到生长因子模块，以驱动细胞周期活性。这种预测的YAP-cMyc轴在大鼠心肌细胞中得到了实验验证，并进一步得到yap刺激的小鼠心脏cMyc开放染色质和mRNA的支持。这个经过验证的计算模型预测了个体调节因子和模块如何协调控制CM增殖。

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

Development 生物-发育生物学

CiteScore

6.70

自引率

4.30%

发文量

433

审稿时长

3 months

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