The spatial organization of chromosomes has long been connected to their polymeric nature and is believed to be important for their biological functions, including the control of interactions between genomic elements, the maintenance of genetic information, and the compaction and safe transfer of chromosomes to cellular progeny. Chromosome conformation capture techniques, particularly Hi-C, and microscopy have provided a comprehensive picture of spatial chromosome organization and revealed new features and elements of chromosome folding. Polymer models and new perturbation data generated in the last two years have led to the identification of novel molecular mechanisms behind large-scale genome organization. Two major mechanisms discovered in the course of this project have moved the field forward. First, is the active (ATP-dependent) process of loop extrusion by Structural Maintenance of Chromosomes (SMC) complexes. This universal mechanism underlies formation of domains in the interphase, and chromosome compaction and segregation in mitosis. Second, is the affinity-mediated interactions between heterochromatic regions that drive spatial compartmentalization of the genome at the scale of the whole nucleus. Proposed project aimed at examining mechanisms of loop extrusion, understanding how gene expression and affect extrusion and hence refold chromosomes, and, finally, developing methods to detect loop extrusion in vivo by combination of polymer simulations and live cell imaging. Together, these aims could show whether and how loop extrusion operates in vivo, opening avenues to understand it functional roles and molecular mechanisms.
The three-dimensional (3D) organization of the human genome is being increasingly appreciated as a critical determinant of gene regulation and genome stability, and defects in 3D genome organization are associated with human diseases such as cancer. This proposal aims to combine computer simulations with analysis of genomic data to unravel molecular mechanisms underlying 3D genome folding.
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| Stanyte, Rugile; Nuebler, Johannes; Blaukopf, Claudia et al. (2018) Dynamics of sister chromatid resolution during cell cycle progression. J Cell Biol 217:1985-2004 |
| Gibcus, Johan H; Samejima, Kumiko; Goloborodko, Anton et al. (2018) A pathway for mitotic chromosome formation. Science 359: |
| Fudenberg, Geoffrey; Imakaev, Maxim (2017) FISH-ing for captured contacts: towards reconciling FISH and 3C. Nat Methods 14:673-678 |
| Flyamer, Ilya M; Gassler, Johanna; Imakaev, Maxim et al. (2017) Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544:110-114 |
| Schwarzer, Wibke; Abdennur, Nezar; Goloborodko, Anton et al. (2017) Two independent modes of chromatin organization revealed by cohesin removal. Nature 551:51-56 |
| Schalbetter, Stephanie Andrea; Goloborodko, Anton; Fudenberg, Geoffrey et al. (2017) SMC complexes differentially compact mitotic chromosomes according to genomic context. Nat Cell Biol 19:1071-1080 |
| Boettiger, Alistair N; Bintu, Bogdan; Moffitt, Jeffrey R et al. (2016) Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature 529:418-22 |
| Goloborodko, Anton; Imakaev, Maxim V; Marko, John F et al. (2016) Compaction and segregation of sister chromatids via active loop extrusion. Elife 5: |
| Khrameeva, Ekaterina E; Fudenberg, Geoffrey; Gelfand, Mikhail S et al. (2016) History of chromosome rearrangements reflects the spatial organization of yeast chromosomes. J Bioinform Comput Biol 14:1641002 |
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