Petri net modeling and simulation of post-transcriptional regulatory networks of human embryonic stem cell (hESC) differentiation to cardiomyocytes.

Stem cells are capable of self-renewal and differentiation into various cell types, showing significant potential for cellular therapies and regenerative medicine, particularly in cardiovascular diseases. The differentiation to cardiomyocytes replicates the embryonic heart development, potentially supporting cardiac regeneration. Cardiomyogenesis is controlled by complex post-transcriptional regulation that affects the construction of gene regulatory networks (GRNs), such as: alternative polyadenylation (APA), length changes in untranslated regulatory regions (3'UTRs), and microRNA (miRNA) regulation. To deepen our understanding of the cardiomyogenesis process, we have modeled a GRN for each day of cardiomyocyte differentiation. Then, each GRN was automatically transformed by four transformation rules to a Petri net and simulated using the software VANESA. The Petri nets highlighted the relationship between genes and alternative isoforms, emphasizing the inhibition of miRNA on APA isoforms with varying 3'UTR lengths. Moreover, in silico simulation of miRNA knockout enabled the visualization of the consequential effects on isoform expression. Our Petri net models provide a resourceful tool and holistic perspective to investigate the functional orchestra of transcript regulation that differentiate hESCs to cardiomyocytes. Additionally, the models can be adapted to investigate post-transcriptional GRN in other biological contexts.