Wake Forest University PS-OP

Chromatin Mobility in Response to DNA Damage

Genomic translocations are well-established drivers of therapy-related myeloid neoplasms (t-MNs). T-MNs have poor outcomes and affect survivors of primary malignancies. It is not possible to predict which patients treated for a primary cancer will develop t-MN, which constitutes a major clinical challenge.

A method to assess the risk of translocations after patient exposures to DNA damaging chemotherapy and radiations would inform therapeutic decisions. Translocations depend on the movements of broken DNA ends on non-homologous chromosomes.

PS-OP investigators developed a method based on diffractive optical elements (DOE) to track photoactivated chromatin reporters and map chromatin motions in the cell nucleus. Their preliminary data show fluctuations in chromatin mobility in response to DNA damage, which may impact genomic translocation frequencies in cells with DNA damage.

The goals for this PS-OP include:

• Develop new methodology to measure chromatin mobility in the 3D nuclear space
• Identify the mechanisms controlling chromatin motions after DNA damage and assess their functional consequences for DNA repair efficacy, repair quality, and translocations frequencies
• Test for clinically relevant associations between chromatin motions and genomic translocations using hematopoietic stem/progenitor cell samples from t-MN patients and healthy donors

Characterizing the physical origins of genomic translocations may yield new methods to predict, and new targets to prevent, genomic rearrangements driving cancer initiation. Beyond the ongoing PS-OP research focused on chromatin motions during DNA repair, PS-OP researchers anticipate broad applicability of novel 3D imaging resources to study chromatin in multiple contexts.

Investigators

Pierre Vidi, Ph.D.
Wake Forest University

Dr. Pierre Vidi is an Assistant Professor of Cancer Biology at the Wake Forest School of Medicine. Dr. Vidi is affiliated to the Wake Forest University Comprehensive Cancer Center. He is a cell biologist who received his Ph.D. from the University of Neuchâtel (Switzerland) in 2006 and trained as a postdoctoral fellow at Purdue University.

Research in his laboratory is centered on cancer prevention. Specifically, he is addressing how tissue architecture and nuclear organization regulate the DNA damage response. In parallel to his mechanistic research with (3D organoids) cell culture models, Dr. Vidi works in tight collaboration with physicists to develop novel imaging approaches, and with clinicians for the translational aspects of his research.

Keith Bonin, Ph.D.
Wake Forest University

Dr. Keith Bonin is a Professor of Physics and Associate Provost for Research & Scholarly Inquiry at Wake Forest University. His original training is in physics, specifically optics, and in the last 15 years has developed biophysics projects. His recent research focuses on the biophysics of cancer, on drug discovery, and optogenetics. He has over 60 publications in physics, optics, and biophysics journals.

Dr. Bonin has a broad experience in microscopy including bright and dark-field fluorescence, total internal reflection fluorescence (TIRF), and differential interference contrast (DIC) microscopy. Dr. Bonin is also an expert in confocal-based microscopy approaches including fluorescence recovery after photobleaching (FRAP) and raster image correlation spectroscopy (RICS).