UC San Diego

Chromatin structure plays a crucial role in various genomic processes in eukaryotic cells, including genome replication, transcriptional silencing, and gene regulation. Extensive studies have focused on the three-dimensional organization of the genome, revealing the presence of topologically associating domains (TADs) and compartments, which are defined by spatial contacts identified through techniques such as Hi-C. However, understanding the direct role of histone modification in shaping the three-dimensional genome structure remains an ongoing challenge.This thesis investigates changing patterns of regulation-associated modules (RAMs) in mouse development to understand the organization and function of RAMs and their boundaries. RAMs, proposed in previous studies using human samples, offer insights into genome organization and regulation. However, comprehensive explanations for RAM formation, functions, and boundary factors are lacking. Using the "findRAM" tool, we have identified RAM regions and boundaries from a dataset of 72 mouse embryonic samples. Pairwise comparisons between tissues at specific time points and between subsequent times within the same tissue have revealed changes in RAMs. Through genome enrichment analysis of these regions, we have identified functional pathways, including cation binding, metal ion binding, and transcription-related pathways. Additionally, consensus RAM (cRAM) regions have been determined for each time point and tissue, highlighting regions that exhibit consistent patterns of RAMs and boundaries. Gene enrichment analysis has provided further support for some of the findings from pairwise comparisons, and these findings align with the potential mechanism of RAM boundary formation proposed in previous research on RAMs. In conclusion, this thesis investigates 3D chromatin modularity through RAM analysis in mouse development data. We have identified pathways and genes potentially involved in RAM boundary formation through computational prediction and discussed improvements for the RAM identification model. These findings contribute to our understanding of the formation and functions of RAMs and boundaries, which are determined by histone modification marks. Ultimately, these findings highlight the connection between the structural and functional modularity of the 3D genome.