UC San Diego

Precise and delicate 3D genome organization is fundamental to cellular homeostasis. Big data generated by high-throughput technologies has granted great opportunities to deepen our understanding of chromatin organization and function, particularly for non-coding DNA sequences which have long been considered “junk DNAs”. This dissertation aims at illuminating the structural importance of the non-coding DNA sequences and elucidating the modular organization of the 3D genome from histone modifications. First, I performed network analysis on Hi-C 3D contact data to identify non-coding DNA regions forming many spatial contacts with other regions (“hubs”) without epigenetic signals that could maintain the global 3D chromatin structure. Furthermore, I employed a small-world network on epigenetic histone modification data to identify a group of active enhancers and promoters harboring many 3D contacts (“hotspots”) which can maintain broad 3D chromatin organization beyond enhancer-promoter interactions. Deletion of hubs and hotspots can produce a profound impact on 3D chromatin organization and cell viability. In addition, through investigation of the histone modification across cell types, I identified the regulation associated modules (“RAMs”) that can not only reflect the modular organization of the 3D genome but also be better aligned with the chromatin function. These studies provide new insights into 3D genome organization and function, navigating future efforts in the mechanistic investigation of the 3D genome.