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.

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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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Preusch, Peter
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Massachusetts Institute of Technology
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Biomed Engr/Col Engr/Engr Sta
United States
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