UC Riverside

The pervasive presence of guanine quadruplex (G4) structures within regulatory regions of the genome has spurred intense research efforts to understand their roles in modulating cellular pathways. Numerous investigations affirm that both DNA and RNA G4s actively partake in pivotal biological processes, including DNA replication, transcription, RNA metabolism, translation, and telomere maintenance. However, further investigation is needed to understand the molecular mechanisms through which these secondary nucleic acid structures modulate biological processes. This dissertation focuses on utilizing bioinformatic analyses of publicly accessible datasets to unravel multifaceted roles of G4 structures in histone modifications, three-dimensional chromatin configurations, RNA metabolism, and telomere maintenance.In chapter 2, we revealed the G4 co-localization pattern with transcription factors and constructed an interaction network of candidate G4-interacting proteins. Moreover, we explored the interplay between G4 structures and histone marks, unveiling G4 structures as active transcription marks and potential regulators for histone modifications. In chapter 3, we conducted an intuitive overlapping analysis of previously published RNAPII ChIA-PET and BG4 ChIP-seq data, and our work revealed a strong positive correlation between RNAPII-linked DNA loops and G4 structures in chromatin. In conjunction with HiChIP-seq and RNA-seq, we unveiled vital role of DNA G4 in RNAPII-associated DNA looping and transcription regulation. In chapter 4, we employed a bioinformatic approach based on the analysis of overlap between RNA G4 (rG4)-seq analysis and eCLIP-seq datasets generated from the ENCODE project. We identified a large number of candidate rG4-binding proteins. We validated that one of these proteins, G3BP1, is a direct binder of rG4 structures, and documented a rG4-dependent function in regulating mRNA stabilities and translation efficiencies. In chapter 5, I proposed a novel approach for identifying putative telomere-binding proteins through enrichment analysis of ChIP-seq datasets covering zinc finger proteins. Three prominent targets, i.e., ZNF24, ZNF316 and ZBTB33, exhibited significant enrichment with telomeric sequences. A detailed examination of ZBTB33 suggested a potential G4-dependent telomere binding activity of the protein. In summary, this dissertation introduces a pioneering bioinformatic approach for investigating the intricate interplay between G4 structures and other cellular regulatory mechanisms, identifying new RNA-binding proteins and probing potential G4-dependent telomere-binding proteins. These insights underscore the regulatory significance of G4 structures and shed light on their intricate roles in the nuanced modulation of cellular processes.