Monday, May 6, 2024
5/6/2024
Project Summary / Abstract My research program centers on defining how cellular forces impinge on chromatin dynamics, gene regulation, and genome integrity, in part through force transduction across the nuclear envelope by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. In the next five years, we plan to investigate both the genetic and non-genetic functions of chromatin with the goal of revealing new insights into the mechanics of chromosomes, the emergent biophysical properties of nuclei, and the mechanisms that underlie nuclear mechanotransduction. As we previously demonstrated the key role that chromatin plays in dictating the emergent mechanical properties of the nucleus, one major focus will be on examining the non- genetic role that the epigenome plays in defining nuclear mechanics. Although altered epigenetic histone modifications are tied to numerous diseases, the potential contribution of these changes to nuclear mechanics is largely unstudied. We will take both targeted and open approaches to leverage our unique tools to assess nuclear mechanics to make fundamental discoveries on this topic. While the attributes of chromatin within the nucleus impacts the nuclear force response, exerting forces on chromatin likely also changes its properties and/or function. We plan to take on two major challenges in this area. First, taking advantage of the tools available in the fission yeast S. pombe, we will define an important biophysical parameter, the genomic distance over which forces can be propagated along a chromosome, represented by the persistence length, or bending rigidity, of chromatin in vivo. Our experiments to date strongly suggest that literature values for chromatin persistence length, largely derived from in vitro studies or relying on simulations, cannot explain the extent to which force can be propagated down the chromosome in living cells. Defining this parameter is not only critical for simulations and the interpretation of experimental data in the chromatin biology field, but is also essential for the study of nuclear mechanotransduction – the process by which forces are translated into gene expression changes. This fundamental line of questioning will position us to take on a second key challenge in the field: defining the contexts and mechanisms by which forces on LINC complexes influence the transcriptome. We will continue to leverage cell lines and mouse models lacking the SUN protein components of LINC complexes to rigorously define genetic targets of direct force transmission and to begin to tackle the black box of the translation of force into gene expression changes. Taken together, this proposed research program will position us to make critical and long-lasting contributions to the field of nuclear mechanobiology.
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