Karolinska Research Lectures: Job Dekker
Karolinska Research Lectures in Nobel Forum: Job Dekker
Howard Hughes Medical Institute, University of Massachusetts Medical School, Program in Systems Biology, Worcester, MA 01605, USA
Title: “Folding, unfolding and refolding of genomes”
Host: Jussi Taipale
In order to understand how the genome operates, we need to understand not only the linear encoding of information along chromosomes, but also its 3-dimensional organization. The 3D organization of the genome is critical for gene regulation, genome stability and faithful transmission of chromosomes to daughter cells. We invented Chromosome Conformation Capture-based technologies to determine how cells fold their chromosomes, to discover the processes that drive the spatial organization of genomes and to identify the mechanisms by which this organization contributes to genome regulation and activity. We discovered that at the nuclear level, chromosomes are compartmentalized into large multi-Mb domains that are either active and open or inactive and closed. These compartments themselves are composed of smaller sub-Mb Topologically Associating domains (TADs) (Dixon et al. 2012, Nora et al. 2012). Finally, long-range gene regulation occurs within TADs through long-range looping interactions between genes and regulatory elements. In mitotic cells we found a completely different chromosome organization: inside compact metaphase chromosomes the genome folds as longitudinally compressed randomly positioned loop arrays, consistent with classical models proposed by the Laemmli lab.
These observations show that during the cell cycle genome folding is dramatically altered, and that the interphase and mitotic state we have described must be interconverted through elaborate folding and refolding pathways. Indeed, detailed time course experiment using highly synchronized cells allowed us to observe how the interphase state is converted into the mitotic state in real time through new folding intermediates. Further, we discovered key roles for several chromosome architectural proteins in this folding pathway. Combined our work is starting to reveal how the genome folds, unfolds and refolds to facilitate gene regulation and chromosome transmission.
Tatiana Goriatcheva, Nobelkansliet, Nobel Forum,
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