FISHing the Genome Architecture
Gabriele Girelli1, Magda Bienko1*
1Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77 Stockholm, Sweden
Deciphering the principles that govern gene expression is central to our understanding of living organisms. Alongside epigenetic marks, the three-dimensional (3D) organization of DNA inside the nucleus has been suggested to play a critical role in establishing specific expression profiles that lead to emergence of unique cellular phenotypes. Our study is focused on deciphering the genome architecture both at chromosome- and sub-chromosome scale in single cells by combining measurements by DNA Fluorescence In Situ Hybridization with mathematical modeling of experimental data. Specifically, we will apply four different chromosome labeling strategies, both data-driven and data-agnostic, with the purpose of identifying the most robust and better performing one. With this approach, we aim to provide a thorough characterization of the position, shape, and internal structure of every human chromosome, as well as inter-chromosome interactions. In parallel, we will verify the standing and intriguing hypothesis that sub-chromosome topologically associated domains (TADs) identified in bulk experiments also exist in single cells. We will design and test four different TAD labeling strategies, with the purpose of answering different questions on the domain organization: from their spatial localization, to the level of complexity of their 3D organization. A confirmation of the existence of such domains, and a characterization of their spatial organization, would constitute a major step forward in the field, shedding light on the genome sub-chromosome architecture at the single-cell level.
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