Identification of key factors of heart regenaration using a systems biology approach.

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Identification of novel key factors of heart development using a systems biology approach

Publication . Machado, Rui Sotero Rodrigues; Futschik, Matthias E.; Bragança, José

Heart diseases are the leading cause of death worldwide. Although surgical interventions can provide valuable options for treatment, current therapies in cardiovascular medicine only delay disease progression. A main reason for this shortcoming is the limited regenerative capacity of the adult human heart. In contrast to many other tissues and organs, the mammalian heart has very limited regenerative capacity. However, it has been observed that neonatal hearts in mice show remarkable capacity to regenerate lost functional muscle tissue, a capacity that rapidly disappears after the first post-natal week. Therefore, the study of heart development might give crucial cues for cardiac regenerative medicine. Heart development or cardiogenesis is a highly complex process with many components that are finely tuned in a precise manner across time and space. Regulation of gene expression plays an important role in this process. To capture this level of regulation, technologies such as microarrays or next generation sequencing provide powerful tools, as they enable the simultaneous measurement of expression levels of thousands of coding and non-coding genes. Although, it is possible to obtain the expression information of several thousand of genes, there is a clear lack of platforms in which research can scan through this information to develop or generate insightful biological questions in the field of heart study. Hence, this doctoral research work has tried to provide different systems biology approaches in order to offer new insights into gene expression events that occur mainly during heart development. These approaches include: (i) the integration of more than 20 published microarray studies related to cardiogenesis and the development of the HeartEXpress database (http://heartexpress.sysbiolab.eu/) to provide an easy and public access to the integrated data; (ii) the integrative analysis of a genome-wide study profiling coding and noncoding genes during embryonic heart development in vivo; (iii) the assessment of transcription factors and miRNAs previously associated to heart development; (iv) the integration and prioritisation of miRNA-mRNA interactions to identify novel miRNAs, mRNAs or miRNAinteractions with potential impact on cardiogenesis; (v) the development of a web-server called HeartmiR (http://heartmir.sysbiolab.eu/), which enables independent query and visualisation of miRNA-mRNA interactions obtained from the in vivo study; and (vi) comparative analysis of in vivo and in vitro studies to obtain further insights into mRNA, miRNA and miRNA-mRNA interactions during embryonic stem cell differentiation and to clarify how the in vitro experiment can be used as a faithful model to study embryonic heart formation. The main contributions of this research work for the study in the heart field are: 1. The development of HeartEXpress, which is a database that integrates the expression of more than 16400 genes and 130 experimental conditions in both human and mouse; 2. The development of HeartmiR, which is a database profiling the expression of 9211 mRNA and 386 microRNAs during the heart development period (from E10.5 to E19.5) and additionally in adult and old murine heart tissue; 3. Identification of the potential of 165 miRNAs to be involved in heart development using different methods of miRNA candidate prioritisation; 4. Identification of 102 miRNA and 214 putative novel miRNA-mRNA interactions relevant for cardiac cell development in vivo and in vitro. Furthermore, from the top20 miRNA with most interactions, 12 of the miRNA (60%) had been already associated to heart related events, indicating promising results for the remaining 8 miRNAs (40%) In summary, I have developed, implemented and applied different systems biology approaches to analyse both publicly available and new generated experimental data. As result, I was able to identify potential novel coding and non-coding key factors important for cardiogenesis that might be utilised as markers or targets in future cardiac regenerative medicine strategies.

2021-12-03Doctoral thesis

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