Executive Summary : | The genomes of higher eukaryotes are organized in a hierarchical fashion, with each layer controlling the accessibility of regulatory DNA sites (genes) and modulating the process of decoding information. The chromosome is the largest structure, while the smallest is the nucleosome, consisting of octameric histone core proteins wrapped by approximately 150 base pairs of DNA. The array of nucleosomes forms a compact chromatin fibre. However, understanding the accessibility of regulatory DNA sequences and gene regulation is linked to chromatin organization at different stages of cell development and varies between healthy and diseased cells. The intrinsically multiscale nature of the chromatin fibre makes understanding the organization of a fibre containing millions of DNA base pairs and investigating the accessibility of regulatory patches of DNA sequences of 10-15 base pairs challenging. This study proposes a novel multiscale approach involving GPU optimized molecular simulations, knowledge-based coarse-grained simulations of the chromatin fibre, curation of large-scale experimental sequencing data, and machine learning approaches to bridge knowledge gaps in 3D genome organization at near base-pair level resolution. The findings will help understand the hierarchical chromatin organization at a resolution, which can pave the way to understanding the principles of 3D organization of the genome in the nucleus, how the organization changes at different stages of cell development, the role of nuclear organization in modulating gene expression and cellular function, and how the genome organization differs in diseased and healthy cell lines. |