UC San Diego

In eukaryotes, the genome is hierarchically packaged inside the nucleus. The 3D organization of chromatin regulates various biological processes such as transcription, DNA replication, and cell division. The accurate gene regulation depends on when and where chromosomal interactions take place in the nucleus. This dissertation focuses on how the genome maintains its function after passing through mitosis and how the nuclear architecture at the nuclear periphery modulates transcription regulation.

A long-standing question in the field is how cells maintain genome structure and function over multiple cell divisions, despite the loss of, for example, chromatin structure and gene expression during mitosis. In the first part of this dissertation, we determine that retention of histone modification binding contributes to accurate transcriptional programs and genome organization. We characterize the role of H3K27ac in the activation of post-mitotic transcription. An increase in H3K27ac binding in anaphase/telophase also shows a positive association with the formation of domains in the genome. Together, these results clarify the mechanism through which the histone modification landscape establishes precise genome regulation across mitosis.

The genome is enclosed in the nuclear envelope membrane, which contains the nuclear pore complex (NPC) components as crucial players in the dynamic organization of the genome and gene regulation. The second part of this dissertation aims to understand how NPC components interact with genomic regions for gene regulation at the nuclear periphery and identify molecular players that participate in NPC-mediated regulation of genome structure and function. We find that a subset of architecture protein CTCF is localized at the NPC and show how it acts as an interacting partner with NPC components to influence transcription. This unexpected, but exciting link provides us insights into how the structures of the nuclear periphery impact genome function.