WP2 will integrate data generated by high-throughput sequencing of the myocardium of aged mice and data of RNA and DNA methylation/hydroxymethylation assessments together with genome-wide analysis of the major histone modcation marks. The broad aim is to define the major epigenetic mechanisms of ncRNA regulation.
Our consortium has already started to integrate sets of data linking gene expression with major epigenetic histone and DNA modifications from cardiomyocytes isolated from aged and stressed myocardium. This work will be expanded to cell types composing the myocardium other than cardiomyocytes, such as endothelial cells and fibroblasts (Task 2.1).
We will further perform exhaustive bioinformatics analysis to identify novel, unannotated ncRNAs involved in cardiac ageing and ageing-related cardiac disease (Task 2.2). After integration into our ncRNA blueprint, a maximum set of 25 ageing-and HF-related ncRNAs will be functionally characterized in vitro in different consortium member laboratories, prior to testing them as therapeutic targets in WP4 (Task 2.3).
We will further test whether this specific set of ageing/HF-regulated ncRNAs can be secreted from the various cell types (Task 2.4) and will then test this set of secreted ncRNAs also in the diagnostics WP3. Finally, cell-cell interactions of secreted ncRNAs will be explored in detail (Task 2.5).