Elucidating the Role for 3D Genome Topology Disruption in Trinucleotide Repeat Expansion Disorders

Women’s Council Recipient
Jennifer Philips-Cremins, Ph.D.
University of Pennsylvania

Women’s Council Seed Grant

DNA from a single human cell is more than 6 feet long when stretched out end to end. Recent technological advances have revealed that the 6 feet long DNA sequence is folded into sophisticated 3-D configurations that enable it to fit into a nucleus the size of the head of a pin. We have uncovered a striking, novel link between 3D genome folding and a class of diseases known as trinucleotide repeat (TNR) expansion disorders. More than 30 TNR disorders exist, including Huntington’s Disease, Fragile X Syndrome, Friedreich’s Ataxia, and Amyloid Lateral Sclerosis. TNR disorders occur via the same underlying mechanism: the DNA sequence is incorrectly duplicated, or expanded, leading to extraneous information in the gene driving the disease. Because the extraneous DNA expansion occurs in a different gene in each disease, TNR disorders have historically been studied independently. We have discovered that nearly all the genes that cause TNR disorders are folded into the same unique 3D structure. This result is important because it provides new insight into the locations in the genome that are particularly vulnerable to mutation by incorrect sequence expansion. Moreover, for one of the TNR diseases, Fragile X Syndrome, we have found that the precise DNA structure around the affected gene is markedly misfolded. The DNA misfolding strongly correlates with gene expression defects that occur in Fragile X Syndrome. One the basis of this preliminary data, we are now funded by the Brain Research Foundation to: (1) investigate the molecular mechanisms driving DNA misfolding in Fragile X Syndrome, (2) Apply our fundamental knowledge to create tools to engineer DNA folding to reverse gene expression defects, and (3) Determine whether 3D genome misfolding contributes to other TNR disorders.  If successful, our work will uncover a fundamentally new mechanism – the 3D misfolding of the DNA – as a key driver of a large cohort of human TNR disorders. Knowledge gained by this work will empower our long-term goal to engineer the 3D genome to reverse gene expression defects in human disease.

Other Grants

Sarah C. Goetz, Ph.D., Duke University
Uncovering a Novel Role for Primary Cilia in Eph/Ephrin Signaling in Neurons
2022 Seed GrantSarah C. Goetz, Ph.D. Duke University Women’s Council Seed Grant Primary cilia are tiny projections from cells that function like an antenna- they receive and may also send…
Erin M. Gibson, Ph.D., Stanford University
Circadian Regulation of Oligodendroglial Senescence and Metabolomics in Aging
2022 Seed GrantErin M. Gibson, Ph.D.Stanford University The brain consists of two main classes of cells, neurons and glia. Glia make-up more than half of the cells in the brain…
Yvette Fisher, Ph.D., University of California, Berkeley
Dynamic Modulation of Synaptic Plasticity During Spatial Exploration
2022 Seed GrantYvette Fisher, Ph.D.University of California, Berkeley The Virginia (Ginny) & Roger Carlson Seed Grant Cognitive flexibility is critical for appropriately adjusting thoughts and behaviors to meet changing demands…
Byoung Il Bae, Ph.D., University of Connecticut
Unique Vulnerability of Developing Human Cerebral Cortex to Loss of Centrosomal Protein
2022 Seed GrantByoung Il Bae, Ph.D.University of Connecticut Carl & Marilynn Thoma Foundation Seed Grant The cerebral cortex is the largest and outermost part of the human brain. It is…