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Skin cancer cell nuclei buckle, bend, and deform as the cells squeeze through narrow constrictions in a dense collagen gel. The more these nuclei can change their shape, the more likely the skin cancer is to become metastatic, crawling through the body to spread to distant sites. Figuring out how these shape changes happen will be a step toward improving diagnosis and treatment of metastatic cancer.

A UT biophysicist has been awarded a $1.84 million Maximizing Investigators’ Research Award (MIRA) from the National Institute for General Medical Science (NIGMS) to investigate how the 3D folded structure of the human genome reacts to physical stress in health and disease.

The award provides funding to operate Rachel Patton McCord’s lab and research program. McCord is an assistant professor in UT’s Department of Biochemistry and Cellular and Molecular Biology.

NIGMS is among the National Institutes of Health (NIH). The MIRA program provides long-term stability—the funding is granted over five years—and allows for flexibility if the direction of a project shifts.

McCord’s project seeks to clarify the role of a chromosome’s structure in its biological response to physical stress, which can inform future disease diagnosis and treatment.

The McCord lab captures human chromosome folding using the Hi-C approach, which maps the pattern of contacts between chromosome regions. In this Hi-C contact matrix the dark orange vs. light orange areas indicate genomic regions of high interaction (dark orange/black) and regions of low interaction (light orange or white). The alternating checkerboard pattern of high and low interactions shows that chromosome regions with high gene activity are kept spatially separate from regions with low gene activity. This particular pattern is the specific folding structure of a human neutrophil chromosome.

While the human genome is often considered simply a linear sequence of protein coding genes, all this genetic information is stored in two-meter-long chromosomes that must be folded and packaged into a 10-micron nucleus. How the chromosomes are folded inside the nucleus affects biological processes, such as gene regulation and DNA repair and replication, as well as the physical properties of the nucleus. Little is known, however, about how the genome structure responds to physical stresses such as X-ray irradiation. Disrupted genome structures can lead to diseases like cancer, so it is important to understand the characteristics, causes, and effects of 3D genome changes.

Using microscopy, cutting-edge sequencing techniques such as chromosome conformation capture, and computational approaches, researchers will investigate the physical impact of nucleus-squeezing cell migration, external forces, X-ray irradiation, and nucleus-deforming proteins on the 3D genome across different cell types.

Building on those results, they hope to build a framework to understand and eventually predict the impact of certain medical treatments and disease conditions on human cell types.

Collaborators on the program include Tongye Shen, associate professor in UT’s Department of Biochemistry and Cellular and Molecular Biology; Adayabalam Balajee at the Oak Ridge Institute for Science and Education; and Jan Lammerding of Cornell University. Their research will be conducted through the Advanced Computing Facility in the UT-Oak Ridge National Laboratory Joint Institute for Computational Sciences as well as UT’s Advanced Microscopy and Imaging Center, Genomics Core, and Bioinformatics Resource Center.

CONTACT:

Karen Dunlap (865-974-8674, kdunlap6@utk.edu)

Amanda Womac (865-974-2992, awomac1@utk.edu)