The three-dimensional (3D) organization of chromosomes is being increasingly appreciated as a critical determinant of gene regulation and genome stability, and dysregulation of chromosome organization is a hallmark of many diseases, most prominently of cancer. Spatial genome architecture in healthy cells and its changes through the cell cycle, development and differentiation remain enigmatic. Recent progress if genomic technologies, particularly development of the Chromosome Conformation Capture methods such as 5C and Hi-C, allowed probing the spatial organization of chromosomes by comprehensive mapping of long-range chromatin interactions. Further progress, however, remains slow in part due to a gap between Hi-C data and 3D models of chromosome organization that can reveal principles of genome folding. Bridging between Hi-C data and polymer models of chromosomes is a major challenge and an objective of our research program. Recently we have developed methods for analysis of Hi-C data, and have successfully developed dynamic polymer models of human mitotic chromosomes and bacterial interphase chromosome, which revealed multiple levels of organization and structural elements not directly visible in the data. Here we propose to make natural next steps by developing multi-scale models of human interphase chromosome in different cell types, and mechanistic models of mitotic condensation that are based on available and emerging genome-wide interaction Hi-C maps. Combined this work has the potential to greatly deepen our understanding of 3D genome organization and reorganization in different cell types and during cell cycle.
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 develop new 3D models of chromosomes organization during interphase and model the process of genome folding into during cell division.
| Nuebler, Johannes; Fudenberg, Geoffrey; Imakaev, Maxim et al. (2018) Chromatin organization by an interplay of loop extrusion and compartmental segregation. Proc Natl Acad Sci U S A 115:E6697-E6706 |
| 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 |
| Dekker, Job; Mirny, Leonid (2016) The 3D Genome as Moderator of Chromosomal Communication. Cell 164:1110-1121 |
| Goloborodko, Anton; Marko, John F; Mirny, Leonid A (2016) Chromosome Compaction by Active Loop Extrusion. Biophys J 110:2162-8 |
| Fudenberg, Geoffrey; Imakaev, Maxim; Lu, Carolyn et al. (2016) Formation of Chromosomal Domains by Loop Extrusion. Cell Rep 15:2038-49 |
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