Hansel-Fröse Aruana F F, Brinkrolf Christoph, Friedrichs Marcel, Dallagiovanna Bruno, Spangenberg Lucia
Laboratory of Basic Stem Cell Biology, Carlos Chagas Institute, Oswaldo Cruz Foundation (FIOCRUZ/PR), Curitiba, Brazil.
Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
J Integr Bioinform. 2025 Jun 23;22(1). doi: 10.1515/jib-2024-0037. eCollection 2025 Mar 1.
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, 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.
干细胞能够自我更新并分化为各种细胞类型，在细胞治疗和再生医学中显示出巨大潜力，尤其是在心血管疾病方面。向心肌细胞的分化复制了胚胎心脏发育过程，有可能支持心脏再生。心肌生成受复杂的转录后调控控制，这种调控影响基因调控网络（GRN）的构建，例如：可变聚腺苷酸化（APA）、非翻译调控区（3'UTR）的长度变化以及微小RNA（miRNA）调控。为了加深我们对心肌生成过程的理解，我们为心肌细胞分化的每一天构建了一个GRN模型。然后，每个GRN通过四条转换规则自动转换为一个Petri网，并使用VANESA软件进行模拟。Petri网突出了基因与可变异构体之间的关系，强调了miRNA对具有不同3'UTR长度的APA异构体的抑制作用。此外，miRNA敲除的模拟能够可视化对异构体表达的后续影响。我们的Petri网模型为研究将人胚胎干细胞分化为心肌细胞的转录调控功能协同作用提供了一个丰富的工具和整体视角。此外，这些模型可用于研究其他生物学背景下的转录后GRN。
