Description:

It has become increasingly clear that the 3D folding of human chromosomes inside the cell nucleus affects numerous fundamental biological processes, including gene regulation, DNA repair and replication, and even the physical properties of the nucleus. Recent research is beginning to define the key molecular factors that build the genome structure, but less is known about how this structure responds to physical stresses experienced by cells and nuclei. The 3D genome structure in healthy cells must withstand or respond to perturbations such as physical forces and nuclear shape changes. Disruptions in genome structure and nuclear architecture can lead to diseases such as cancer or premature aging, and so my research seeks to determine the characteristics, causes, and effects of these 3D genome changes. By integrating microscopy, computational analysis, and the sequencing-based technique chromosome conformation capture (Hi-C) approach, we probe properties of human 3D genome architecture in conditions such as cell migration through narrow constrictions and direct expansion of isolated nuclei in low salt. We observe striking differences in chromosome spatial compartmentalization in melanoma cells that have passed repeatedly through tight constrictions. These constricted migration 3D genome signatures likely arise through a combination of both selection and changes induced by the constricted migration process. Some chromosome structure shifts are associated with altered gene expression while others may be more physical in nature. We find that a loss of interaction frequency within heterochromatic regions is a shared feature between melanoma and breast cancer cells. When we instead expand nuclei by decompacting the chromatin fiber in low salt, we observe an overall preservation of chromosome contacts across length scales, but a similar loss of heterochromatic compartment strength as we observed after constricted migration. Our observations begin to shed light on the robustness of the 3D genome structure to perturbation and how the network of 3D contacts in the genome can accomplish both gene regulatory functions and contribute to necessary physical properties of the nucleus. 

Rachel Patton McCord, Ph.D.

Rachel Patton McCord received her B.S. in Biophysics from Davidson College and a Ph.D. in Biophysics from Harvard University.  She began working with large scale genomic data during her doctoral work under the mentorship of Dr. Martha Bulyk, analyzing transcription factor sequence preferences from protein binding microarray data.  Realizing that information along the linear DNA sequence has limited ability to explain complex human gene expression, she pursued postdoctoral research exploring genome architecture in Dr. Job Dekker’s lab at UMass Medical School.  She joined the Biochemistry & Cellular and Molecular Biology faculty at the University of Tennessee Knoxville in 2016, where her lab combines experiments and computational analyses to study the influence of physical perturbations on 3D genome structure.