Three-dimensional (3D) folding and spatial organization of chromosomes including genome positioning and organization of several sub-structures of chromatin such as chromatin domains and territories are responsible for gene expression and gene regulation. However, a proper understanding on the relationship between genome organization and genome function in diseased cells is still lacking. Our current understanding on chromatin structure has been hindered by the diffraction limit of light (250 nm), which falls far short of enabling us to visualize chromatin structure. Recently, Wu lab has developed a pioneering technique called OligoSTORM, which circumvents this limitation and enables visualization of chromatin at unprecedented spatial resolution, at the nanoscale (<20nm resolution). Here my goal is to investigate the 3D spatial organization and packaging of chromosomal territories of trisomy 21 in the nucleus of Down syndrome (DS) cells, using a combination of a microscopy, including OligoSTORM, sequencing-based approaches, such as chromosome conformation capture (Hi-C), as well as chromatin modeling. I want to explore correlations among chromosome organization, patterns of gene positioning, and disease phenotypes in the context of Down syndrome pathology and therapeutics. I will be asking, how does the aneuploid addition of genomic material affect the organization of the genome? Does the imbalance of gene expression caused by aneuploidy correspond to changes in genomic structure? Since I will be using imaging technologies that have not been widely or at all implemented for imaging aneuploid genomes, I hope to open new avenues of investigation. The results of these projects may provide new insights into the nano-architectures of the chromosomal abnormalities that characterize diseased cells.
Huy Q. Nguyen, Shyamtanu Chattoraj, David Castillo, Son C. Nguyen, Guy Nir, Antonios Lioutas, Elliot A. Hershberg, Nuno M. C. Martins, Paul L. Reginato, Mohammed Hannan, Brian J. Beliveau, George M. Church, Evan R. Daugharthy, Marc A. Marti-Renom & C.-ting Wu. Nat Methods 17, 822–832 (2020). https://doi.org/10.1038/s41592-020-0890-0
Guy Nir, Irene Farabella, Cynthia Pérez Estrada, Carl G. Ebeling, Brian J. Beliveau, Hiroshi M. Sasaki, S. Dean Lee, Son C. Nguyen, Ruth B. McCole, Shyamtanu Chattoraj, Jelena Erceg, Jumana AlHaj Abed, Nuno M. C. Martins, Huy Q. Nguyen, Mohammed A. Hannan, Sheikh Russell, Neva C. Durand, Suhas S. P. Rao, Jocelyn Y. Kishi, Paula Soler-Vila, Michele Di Pierro, José N. Onuchic, Steven P. Callahan, John M. Schreiner, Jeff A. Stuckey, Peng Yin, Erez Lieberman Aiden, Marc A. Marti-Renom, C.-ting Wu. PLOS Genetics, December 26, 2018 https://doi.org/10.1371/journal.pgen.1007872
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