Genetic information is encoded in DNA molecules, which can be very long in species with large genomes. The DNA molecules hence need to be properly organized inside the tiny volume of cells. This three-dimensional organization of DNA molecules needs to enable long-range interactions between distant DNA segments, which play fundamental roles in the function of genomes, including gene regulation, genetic recombination, and transmission of the genome across cell generations.
Key methodological advances over the last 10 years have led to tremendous progress in understanding the molecular mechanisms shaping intramolecular chromosome loop structures. In contrast, while topological interactions across separate chromosomal DNA molecules are well known to contribute to essential biological processes, limitations in our ability to distinguish specific chromosome conformations across paired molecules has hindered research into the underlying mechanisms. Our development of sister chromatid-sensitive chromosome conformation capture has recently allowed to distinguish inter-molecular contacts between sister chromatids from intra-molecular contacts forming loops on individual sister chromatids.
In this project, we aim to develop a next-generation version of sister-chromatid-conformation capture to map the conformation of sister chromatids with unprecedented resolution. We will develop a machine learning framework for integrated analysis of chromosome conformation and chromatin fiber composition. We will also develop a super-resolution imaging approach to trace sister-chromatid fibers to reveal conformational variability in individual cells.
With these new technologies, we aim to understand the molecular mechanisms shaping replicated genomes. Combining conformation analysis with profiling of genomic localization will reveal how different molecular factors organizing loops and linkages interact to shape replicated chromosomes. We also aim to uncover how sister-chromatid conformation contributes to physiological processes. Perturbations of sister chromatid conformations will reveal how trans-molecular topological interactions contribute to DNA repair, gene regulation, and resolution of sister-chromatid fibers for chromosome segregation in mitosis.
Our work will establish innovative technologies that are applicable to diverse biological studies. Furthermore, by gaining insights into the basic mechanisms of life, our study will lay the foundation for future work aiming at solving specific problems, e.g. in biomedical applications.
