Life Sciences Faculties

In recent years the cell nucleus emerged as a dynamic mechanosensor capable of sensing and transducing mechanical signals into cellular responses to facilitate homeostasis and adaptation to changing environmental conditions. The constantly beating heart has a remarkable ability to adapt its structure and contractility in response to changes in mechanical load. I am introducing unique, live, and dynamic imaging approaches to investigate how nuclei in the mature heart can provide such mechano-protection and mechano-regulation of the genome. I will present a novel assay to couple cytoskeletal to nuclear strain transfer in the beating cardiomyocyte, and its further application to decipher mechanisms of nuclear damage in dilated cardiomyopathy caused by mutations in the LMNA gene (LMNA-DCM). This work pinpoints localized microtubule-dependent forces, but surprisingly not actomyosin contractility, as drivers of nuclear damage in LMNA-DCM, highlighting new therapeutic avenues. I will further discuss the role of mechanical signaling in spatial organization of the genome within the nucleus, to regulate transcriptionally active and repressed hubs, and downstream gene expression.