Project Summary/Abstract:
The 3D folding of human chromosomes inside the 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 little 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, nuclear shape
changes, and DNA damaging insults, like radiation. Disruptions in genome structure and nuclear architecture
can lead to diseases such as cancer or premature aging, so it is important that we determine the characteristics,
causes, and effects of 3D genome changes. Often, disease-related changes in 3D genome organization are
considered in isolation, i.e. “this change occurs in cancer,” but this perspective may miss common underlying
mechanisms that govern the 3D genome across many biological situations. My research program seeks to
develop an integrative view of the changes that chromosomes experience in response to physical disruptions
through a complementary set of projects. Our overarching goals are to understand how different levels of 3D
genome structure change in response to nuclear shape changes and DNA damaging radiation 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. To this end, we will integrate microscopy, cutting edge
sequencing-based techniques such as chromosome conformation capture (Hi-C), and computational
approaches to investigate 3D genome disruptions in several systems, including: 1) cells exposed to DNA
damaging X-ray irradiation, 2) the initial states and adaptations of the 3D genome necessary for cell nuclei to
squeeze through tight spaces during confined migration, and 3) the aspects of genome structure that are
disrupted and maintained during cellular aging in a lamin-mutant progeria cell. Our research program has
yielded preliminary evidence that motivates further study of these systems: we have determined that the cell
actively protects its 3D genome structure after X-ray damage and that the 3D genome folding state influences
whether cancer cell nuclei can squeeze through tight spaces during metastatic migration. These results show
that a comprehensive understanding of genome structure changes is necessary to better understand disease
initiation and progression. Analyzing genome structure changes across systems will provide a unique,
integrated view of what types of genomic regions or structures are the most robust or fragile and the degree of
dependence between genome structures at different length scales. All these results will help us build a
framework in which we can understand, and eventually predict, the impact of certain treatments or conditions
on human cell types, depending on their initial genome folding state. This framework will open avenues for
future chromosome structure-based disease diagnosis and treatment.
