Description du projet
Étudier les interactions entre les complexes des sarcomères et des splicéosomes ainsi que leur lien avec l’insuffisance cardiaque
La fonction cardiaque s’adapte à la charge mécanique en utilisant un réseau de facteurs d’épissage qui régule de multiples ARNm cibles, modifiant la biomécanique, l’activité électrique, le métabolisme, la signalisation et la croissance. Le splicéosome contient un complexe d’ARN et de protéines de liaison à l’ARN, dont l’activité est régulée pour adapter l’expression des isoformes cardiaques et la mécanique des sarcomères. Le projet MERAS, financé par le CER, se penchera sur la mécanorégulation de l’épissage cardiaque en lien avec les maladies cardiaques en utilisant une analyse multi-omique ainsi qu’un séquençage isoforme et mécanique de cellules uniques. L’objectif du projet consiste à étudier les interactions fonctionnelles entre les complexes macromoléculaires des sarcomères et des splicéosomes en vue d’évaluer le potentiel de la mécanotransduction en tant que cible thérapeutique pour lutter contre l’insuffisance cardiaque.
Objectif
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.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
13125 Berlin
Allemagne