RII Track-4: Mechanical Regulation of Intra-Nuclear Mechanics and Gene Transcription

All living organisms, from animals to single cells, adapt to environmental challenges to survive and function. In humans, for example, mechanical signals generated by exercise is universally recognized to combat obesity, maintain a healthy musculoskeletal system and improve quality of life. However, at the cellular level, how these mechanical signals accomplish their function remains as a critical knowledge gap that precludes us from understanding its underlying principles. The aim of this project, through using state of the art technologies, is to address this knowledge gap and promote scientific progress. Understanding how environmental forces (wind, solar, electrical and mechanical) regulate cell function is a first critical step in reverse engineering the cell functions in order to generate next generation of solutions for broad range of problems from health care to energy sustainability. To increase the positive long-term impact on environmental and other goals of the nation, tools generated will be disseminated across many platforms: undergraduate students will be trained through yearly internships, concepts will be transferred via graduate classes and new collaborations will be formed between researchers during summer workshops. The proposed research program will be an excellent platform to fascinate next generation students and researchers.

Cellular adaptation to the local mechanical environment requires orchestration from the moment of reception to distal gene transcription. Central to this function, the nucleus responds to external stimuli or its molecular transducers by regulating intra-nuclear organization that ultimately determines gene expression to control cell function and fate. While knowledge about individual processes including, mechanoreception, genomic organization and transcription are exceedingly detailed, efforts to unify this information into a set of deterministic rules is lacking. The long-term goal of this research is to generate predictive models of how the chromatin nano-environment adapts to the cellular macro-environment to control gene expression. As a first critical step in answering this overarching question, this project will focus on currently unknown spatial relationships between local nuclear stiffening and mRNA transcription in living cells. By uniquely combining deformation microscopy method with the tracking of mRNA transcription at a single gene locus, this project aims to correlate full-field strain in the live nucleus with the real-time mRNA transcription in mechanically challenged stem cells. Correlations between subnuclear mechanics and mRNA transcription will advance the scientific knowledge on how external mechanical force regulates cell function. The PI aims to receive training to transfer the deformation microscopy technique into Boise State University and combine it with live mRNA tracking and adipogenic MSC differentiation model.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.