Mapping a genome-scale in vivo knockout screen to a mechanistic network model identifies VAV2, RASA1, and LEPR as regulators of cardiomyocyte hypertrophy
Cardiomyocyte hypertrophy is a leading clinical predictor of heart failure, yet newly identified candidate genes often remain disconnected from the signaling mechanisms that govern cardiomyocyte growth. We developed a computational-experimental pipeline that integrates genome-scale mouse knockout phenotypes with a logic-based differential equation model of hypertrophic signaling. Among 9,605…
Cardiomyocyte hypertrophy, the enlargement of heart muscle cells, is a key indicator of heart failure. Despite the identification of potential genes linked to this process, the underlying signaling mechanisms often remain unclear. To address this gap, researchers have devised a computational-experimental pipeline that combines genome-wide knockout studies in mice with a mathematical model of hypertrophic signaling.
By screening 9,605 genes from the International Mouse Phenotyping Consortium database, the researchers identified 939 knockout lines that led to abnormal heart development. Further analysis focused on sub-phenotypes related to hypertrophy and expanded these findings into a network model that connected 37 genes to this signaling pathway. Virtual knockdown experiments confirmed the roles of five genes, including LRIG1 and CBL as potential negative regulators, and VAV2, RASA1, and LEPR as possible positive regulators.
A deeper dive into the network structure revealed that these genes interact with various signaling routes, including those involving receptors, the Ras pathway, PI3K-AKT pathway, and MAPK signaling. To validate these findings in a living system, the researchers used siRNA to temporarily suppress the activity of VAV2, RASA1, or LEPR in neonatal rat cardiomyocytes.
The results showed that the depletion of these proteins reduced the growth of cells in response to phenylephrine, suggesting their direct contribution to hypertrophy.
The quantitative assessment of heart structure in mouse models further supported the predicted effects of VAV2 and LEPR knockouts, while RASA1 knockouts might exhibit age-dependent hypertrophy. This study demonstrates the power of integrating network models with experimental data to bridge the gap between in vivo phenotypic screens and our understanding of the molecular mechanisms governing cardiomyocyte growth.
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