Chromatin motions in response to DNA damage
How is chromatin dynamics changing in response to DNA damage, and what are the functional consequences of DNA motions for DNA repair outcomes?
We use live cell microscopy to address these questions. A custom structured illumination system is used to photoactivate and track microdomains of chromatin. Temporal precision relative to DNA damage induction is achieved using a miniature X-ray source on the microscope.
The translational goal of this project is to determine if chromatin motions are necessary for the biogenesis of genomic translocations, which are major drivers of secondary cancers, to ultimately predict (and possibly prevent) genomic rearrangements in cells with multiple DNA breaks caused by chemotherapeutics. This project is part of the NCI's Physical Sciences - Oncology Network (PS-ON).
Selected publications:
We use live cell microscopy to address these questions. A custom structured illumination system is used to photoactivate and track microdomains of chromatin. Temporal precision relative to DNA damage induction is achieved using a miniature X-ray source on the microscope.
The translational goal of this project is to determine if chromatin motions are necessary for the biogenesis of genomic translocations, which are major drivers of secondary cancers, to ultimately predict (and possibly prevent) genomic rearrangements in cells with multiple DNA breaks caused by chemotherapeutics. This project is part of the NCI's Physical Sciences - Oncology Network (PS-ON).
Selected publications:
- Nanoscale histone localization in live cells reveals reduced chromatin mobility in response to DNA damage.
Liu J*, Vidi PA*@, Lelievre SA, Irudayaraj JM@.
Journal of Cell Science. 2015 128(3):599-604. [link]
Description of transient changes in chromatin diffusion speed after DNA damage. - Structured illumination to spatially map intracellular molecular motions.
Bonin K@, Smelser A, Salvador-Moreno N, Holzwarth G, Wang K, Levi P, Vidi PA@.
Journal of Biomedical Optics. 2018 23(5):1-8. [link]
A novel optical system to track chromatin motions. - Performance of deep learning restoration method for the extraction of particle dynamics in noisy microscopy image sequences. Kefer P, Iqbal F, Locatelli M, Lawrimore J, Zhang M, Bloom K, Bonin K, @, Liu J@.
Mol. Biol. Cell. 2021 32(9):903-914. [link]
An objective approach to evaluate and 'sanity check' deep learning algorithms used for image analysis. - Characterization and implementation of a miniature X-ray system for live cell microscopy.
Prajapati S, Locatelli M, Sawyer C, Holmes J, Bonin K, Black P, Vidi PA@.
Mutat Res. 2021 824:111772. [link]
Integration of an irradiator on the microscope to study early responses to DNA damage. - Three-dimensional tracking using a single-spot rotating point spread function created by a multiring spiral phase plate.
Bonin K@, Prasad S, Caulkins W, Holzwarth G, Baker SR, Vidi PA.
Journal of Biomedical Optics. 2022 27(12):126501. [link]
Tracking chromatin loci in 3D using a new multifocal imaging approach. - DNA damage reduces heterogeneity and coherence of chromatin motions.
Locatelli M, Lawrimore J, Lin H, Sanaullah S, Seitz C, Segall D, Kefer P, Salvador Moreno N, Lietz B, Anderson R, Holmes J, Yuan C, Holzwarth G, Bloom KS, Liu J, Bonin K@, Vidi PA@.
Proc Natl Acad Sci USA. 2022 119(29):e2205166119. [link]
Spatial dependency of the chromatin response to DNA damage.
Structured illumination to quantify chromatin motions
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Miniature X-ray source integrated to the microscope
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Impact of the cell microenvironment on the DNA damage response
Obesity and high mammographic density both elevate breast cancer risk and are characterized by profound changes in the extracellular matrix (ECM). Stiffening of the ECM is also a hallmark of the initiation of hepatocarcinoma. What are the molecular connections between drifts in the chemical nature and physical properties of the cell microenvironment and genome maintenance?
We address these questions using 3D cell culture models and human tissues. This fundamental knowledge is needed to advance primary prevention.
We address these questions using 3D cell culture models and human tissues. This fundamental knowledge is needed to advance primary prevention.
Selected publications:
- Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response.
Vidi PA@, Chandramouly G, Gray M, Wang L, Liu E, Kim JJ, Roukos V, Bissell MJ, Moghe PV, Lelievre SA@.
Journal of Cell Science. 2012 125(Pt 2):350-361. [link] - Discovery that cell-ECM interactions regulate the DNA damage response, with implication of a nuclear structural protein (NuMA).
- NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks.
Vidi PA@, Liu J, Salles D, Jayaraman S, Dorfman G, Gray M, Abad P, Moghe PV, Irudayaraj JM, Wiesmuller L, Lelievre SA@.
Nucleic Acids Research. 2014 42(10):6365-6379. [link] - The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair.
Salvador Moreno N, Liu J, Haas KM, Parker LL, Chakraborty C, Kron SJ, Hodges K, Miller LD, Robinson PL, Lelièvre SA, and Vidi PA@.
Nucleic Acids Research. 2019 47(6):2703-2715. [link]
These publications define a novel role for NuMA in DNA repair. - Elevated leptin disrupts epithelial polarity and primes cancer initiation in the mammary gland.
Tenvooren I, Jenks MZ, Rashid H, Cook KL, Muhlemann JK, Sistrunk C, Holmes J, Wang K, Bonin K, Hodges K, Lo HW, Shaikh A, Camarillo IG, Lelièvre SA, Seewaldt V, Vidi PA@.
Oncogene. 2019 38(20):3855-3870. [link]
This paper shows that metabolic imbalance in obesity disrupts the normal organization of the breast epithelium, a critical step in cancer initiation. - Diet Alters Entero-Mammary Signaling to Regulate the Breast Microbiome and Tumorigenesis.
Soto-Pantoja DR, Gaber M, Arnone AA, Bronson SM, Cruz-Diaz N, Wilson AS, Clear KYJ, Ramirez MU, Kucera GL, Levine EA, Lelièvre SA, Chaboub L, Chiba A, Yadav H, Vidi PA, Cook KL@.
Cancer Res. 2021 81(14):3890-3904 [link]
This collaborative study provides a mechanistic link between (1) shifts in gut and mammary microbiomes caused by obesity and (2) breast cancer risk. - Reversion of breast epithelial polarity alterations caused by obesity.
Holmes J, Gaber M, Jenks MZ, Wilson A, Loy T, Lepetit C, Vitolins MZ, Herbert BS, Cook, KL, Vidi PA@.
NPJ Breast Cancer. 2023 9(1):35 [link]
Genotoxicity of environmental pollutants
Children, like adults, are exposed to pesticides and other toxic chemicals in their environment. What are the consequences of these exposures for their health?
We combine pesticide exposure data with DNA damage detection in plucked hair follicles – a molecular marker of risk for cancer and other diseases. Understanding which pesticides (or pesticide mixtures) lead to genotoxic effects is essential for policymaking in environmental health.
We combine pesticide exposure data with DNA damage detection in plucked hair follicles – a molecular marker of risk for cancer and other diseases. Understanding which pesticides (or pesticide mixtures) lead to genotoxic effects is essential for policymaking in environmental health.
Selected publications:
- Personal samplers of bioavailable pesticides integrated with a hair follicle assay of DNA damage to assess environmental exposures and their associated risks in children. Vidi PA@, Anderson KA, Chen H, Anderson R, Salvador-Moreno N, Mora DC, Poutasse C, Laurienti PJ, Daniele SS, and Arcury TA.
Mutation Research. 2017 822:27-33. [link]
A novel noninvasive approach to relate environmental exposures and DNA damage in epithelial cells (of children). - Follicular DNA damage and pesticide exposure among Latinx children in rural and urban communities.
Lepetit C, Gaber M, Zhou K, Chen H, Holmes J, Summers P, Anderson KA, Scott RP, Pope CN, Hester K, Laurienti PJ, Quandt SA, Arcury TA, Vidi PA@.
Exposure and Health. 2023 822:27-33. [link]
Results from our first study with children participants in North Carolina.
