PRBB-CRG Sessions Jan Lammerding

14/06/202412:00MARIE CURIEPRBB-CRG SessionsJan LammerdingWeill Institute for Cell and Molecular Biology & Meinig School of Biomedical Engineering, Cornell University"Nuclear mechanobiology – from striated muscle disease to ultrarapid cellular mechanosensing"Host: Verena RuprechtAbstract:The nucleus is the characteristic feature of eukaryotic cells and houses the genomic information of the cell. The Lammerding laboratory is investigating how physical forces acting on the nucleus can challenge the integrity of the nucleus, alter its structure, and cause genomic, transcriptomic, and other functional changes. In this seminar, I will discuss our findings that highlight the importance of the nuclear envelope proteins lamins A/C in mediating nuclear stability and mechanotransduction in mechanically stressed cells and tissues, and how lamin mutations result in reduced nuclear stability and increased nuclear damage in striated muscle cells, which may explain the muscle-specific defects in many diseases caused by lamin mutations (laminopathies). Our data demonstrate that reducing cytoskeletal forces on the fragile lamin A/C mutant nuclei by disrupting the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is sufficient to reduce nuclear damage in striated muscle tissue and to improve cardiac function and survival in multiple mouse models of lamin A/C related striated muscle disease. Furthermore, by combining cyclic strain application with precision nuclear run-on sequencing (PRO-seq), a novel transcriptome sequencing technique that, unlike traditional RNA sequencing, enriches for nascent RNA transcripts and simultaneously provides a base-pair resolution map of active RNA polymerases, and Omni-ATAC, an improved chromatin accessibility assay, we recently established an experimental pipeline to detect rapid, genome-wide changes in chromatin organization and transcription in response to cyclic mechanical strain. Our studies indicate that cyclic strain application results in the transcription of numerous mechanoresponsive genes within less than 2 minutes, which is faster than the expected time for typical mechanoresponsive cytoplasmic signaling pathways to reach the nucleus, and that the mechanoresponsive genes are already poised for gene transcription. These findings point to an exciting, previously unrecognized role of the nucleus in regulating the activation of mechanoresponsive genes.