Project description DEENESFRITPL Investigation of the interaction between the sarcomere and spliceosome complexes and their link to heart failure Cardiac function adapts to mechanical load utilising a splice factors network that regulates multiple target mRNAs, changing biomechanics, electrical activity, metabolism, signalling, and growth. The spliceosome contains a complex of RNAs and RNA binding proteins, whose activity is regulated to adapt cardiac isoform expression and sarcomere mechanics. The ERC-funded MERAS project will explore the mechanoregulation of cardiac splicing related to heart disease using multi-omics analysis and single-cell isoform sequencing and mechanics. The project objective is to investigate the functional interaction of the sarcomere and spliceosome macromolecular complexes to evaluate mechanotransduction as a potential therapeutic target in heart failure. Show the project objective Hide the project objective Objective To adapt cardiac function in response to mechanical load, a network of splice factors concertedly regulates multiple target mRNAs that affect biomechanics, electrical activity, metabolism, signaling, and growth. It includes the splice regulator RBM20, with mutations causing severe cardiomyopathy, as well as its substrate titin, whose >350 exons are differentially joined to adjust the elastic properties of the sarcomere and thus ventricular filling. In the spliceosome, diverse RNAs and RNA binding proteins interact in macromolecular complexes, but how their activity is regulated to adapt cardiac isoform expression and sarcomere mechanics has remained elusive.We have adapted localization proteomics to study macromolecular complexes in vivo at physiological expression levels, which has previously not been possible. Our titin-BioID knock-in mice have provided the first census of the sarcomeric proteome and uncovered a previously unknown connection between sarcomeric mechanotransduction and mRNA processing in the nucleus. This unexpected link is the basis of our hypothesis that altered strain of the titin filament is communicated to the nucleus where the spliceosome adapts titin isoform expression to adjust sarcomere elasticity. This proposed regulatory feedback loop would elegantly resolve the question of how sarcomeres adapt to mechanical load.Here, we will explore how the mechanoregulation of cardiac splicing contributes to heart disease in a functional multi-omics approach and develop technologies that combine single cell isoform sequencing and mechanics to examine how heterogeneity of the mechanical microenvironment determines isoform expression in the individual cardiomyocyte.The overall scientific goal of the proposed work is to investigate the functional interaction of two macromolecular machines – the sarcomere and the spliceosome – and to evaluate mechanotransduction as a potential therapeutic target in heart failure with increased ventricular stiffness. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicssocial sciencessociologydemographycensusnatural sciencesbiological sciencesbiophysicsnatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesclinical medicinecardiology Programme(s) HORIZON.1.1 - European Research Council (ERC) Main Programme Topic(s) ERC-2021-ADG - ERC ADVANCED GRANTS Call for proposal ERC-2021-ADG See other projects for this call Funding Scheme ERC - Support for frontier research (ERC) Coordinator MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC) Net EU contribution € 2 499 999,00 Address Robert rossle strasse 10 13125 Berlin Germany See on map Region Berlin Berlin Berlin Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
