Xi Lu: Integrative Modeling of Epigenetic Regulation in Human Disease

Abstract

Glioblastoma is the most common and aggressive primary brain tumor. Standard of treatment prove ineffective, leading to tumor recurrence and an average survival rate of 14 months. This treatment resistance is attributed to both inter-tumor and intra-tumor heterogeneity observed across diverse tumor samples and within individual cells. Dravet syndrome is a severe early-onset refractory epilepsy characterized by an unfavorable long-term outcome and medication resistance. In this thesis, patient-derived stem cell culture models were utilized to study both diseases. We employed sequencing technologies, including the Assay for Transposase-Accessible Chromatin with high-throughput sequencing and single-cell multi-omics technologies to delve into cell-lineage-controlled epigenetic regulation in glioblastoma, the mechanism behind the recurrence of glioblastoma and epigenetic dysfunction in Dravet syndrome patients during neural development. 

In Paper I, we validated the impacts of the developmental origin on human glioblastoma stem cell groups and revealed conserved epigenetic regulation between mouse and human glioblastoma stem cells through cross-species epigenome analysis. Human glioblastoma stem cell clusters exhibited distinct functional properties and have significant clinical outcomes. 

In Paper II, we discovered that the infiltrative region of the primary bulk tumor was more invasive and less self-renewing and tumorigenic compared to its paired bulk culture. Single-cell multi-omics sequencing showed an inclination towards astrocyte-like/mesenchymal-like cell states in edge cultures across all patients from transcriptomic aspect and chromatin-accessibility profiles highlighting edge cells associated with cell invasion, inflammation, and myeloid cells. 

In Paper III, we offered critical insights into the dysfunction of regulatory chromatin in Dravet syndrome patients using time-series ATAC sequencing. We observed that heathy individuals and Dravet syndrome patients were regulated by different transcription factors during development. Treatment with VPA effectively reshaped the chromatin landscape and rescued the observed dysfunctional development in some Dravet syndrome patients.