CAREER: Mechanical Regulation of Chromatin Motion

Indiana University, Bloomington IN

Investigators

Abstract

The overarching goal of this CAREER award is to understand how the chromatin motion in human cell nucleus responds to external mechanical stimuli. Chromatin is the mixture of DNA and proteins that form the chromosomes in the cells of humans and other organisms. The nanoscale movement of chromatin may modulate the interaction of DNA in the cell with regulatory molecules, which impacts many fundamental cell functions, such as DNA replication, DNA repair, transcription and, finally, gene expression. Understanding the mechanical regulation of the chromatin dynamics has the potential to power the engineering of living systems and to create new transformative strategies for the treatment of disease. This project will in particularly focus on the long-lasting question in nuclear mechanotransduction, i.e., if the change of chromatin motion in the nucleus is directly driven by the pico-Newton forces transmitted through the cell or is indirectly dominated by the diffusion throughout the cytoplasm. The preliminary data clearly concludes that both intracellular tensions and chromatin dynamics are mechanosensitive and are possibly connected. This project will design and develop a new imaging platform that can simultaneously quantify the intracellular tension and chromatin motion under mechanical stimuli. In addition, this project will develop an experiment to use a magnetic bead to mechanically disturb the live cell with high sensitivity and resolution. With this, it is expected to observe the spatiotemporal changes of the intracellular tension and chromatin motion in real-time. This project focuses on the dynamic signature of the chromatin, with an exquisitely sensitive imaging system and broadly applicable analytic tools for quantitative fluorescent imaging. In addition, this project will also develop a consortium that integrates high performance computational tools and cyberinfrastructure into biological research. This project will serve as a vehicle to increase the awareness of educational opportunities and career paths in computational biology and biophysics for high school students and undergraduates in related disciplines. An annual and free summer camp of bioimage informatics, which is part of the ACS SEED project, will be offered to high school students from economically disadvantaged families. The PI will integrate computational components into this project with the undergraduate teaching. Finally, an undergraduate research internship is developed on the IU-MSI initiative, which aims to attract underrepresented students from minority serving institutes, by providing short-term internship opportunities for the project. 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.