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.
Footnotes
Author contributions
Conceptualization: B.N.H., J.J.S.; Data curation: M.J.W.; Formal analysis: A.M.W.; Investigation: B.N.H., L.A.W., R.N.P., M.C., M.J.W., J.J.S.; Methodology: B.N.H., L.A.W., A.M.W.; Supervision: M.C., J.J.S.; Writing – original draft: B.N.H.; Writing – review & editing: L.A.W., M.C., J.J.S.
Funding
This work was supported by National Institutes of Health grants R01HL162925 and R01HL160665 to J.J.S. and a National Science Foundation Predoctoral Fellowship to B.N.H. Deposited in PMC for release after 12 months.
Data availability
Code and documentation for the model are available at https://github.com/saucermanlab/Cardiomyocyte-Proliferation-Network.
