Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular, Cellular, and Developmental Biology

First Advisor

Jacob, Yannick

Abstract

Genomic stability is a cornerstone of cellular integrity, with implications spanning genetic engineering, epigenetic regulation, and disease modeling. However, most studies rely on yeast or mammalian models, leaving significant gaps in our understanding of plant chromatin biology and genome stability mechanisms. Exploring the conserved and divergent processes regulating genome stability in plants has become increasingly important, especially as global climate change threatens crop yields and biodiversity. Furthermore, the developmental resilience of plants provides a unique opportunity to study genes essential in mammals, offering translational insights for agriculture and human health. This dissertation investigates the molecular and genetic mechanisms underpinning T-DNA concatenation and the epigenetic disruptions caused by the histone variant mutation H3.1K27M, using Arabidopsis thaliana as a model system. The initial chapters focus on identifying and characterizing the molecular triggers of T-DNA concatenation, a process essential for the stable integration of foreign DNA into plant genomes. Through detailed analysis of T-DNA concatenation architecture and targeted screening of genetic elements, key DNA structures driving concatenation are elucidated. Subsequent work examines the temporal and genetic regulation of this process, highlighting critical windows and genetic factors responsible for the formation of T-DNA concatenation. To explore the broader implications of histone modifications in genomic instability, an Arabidopsis model expressing the oncohistone H3.1K27M was developed and characterized. This model facilitated a comprehensive analysis of H3.1K27M's role in DNA repair responses, chromatin remodeling, and genomic instability. Findings reveal that H3.1K27M induces DNA damage through misregulation of the TONSL/TSK-H3.1 pathway, linking histone modifications to compromised genome integrity. These discoveries offer new insights into the molecular basis of epigenetic misregulation and its parallels with human diseases, including diffuse midline gliomas (DMG). This work advances our understanding of DNA integration mechanisms and the epigenetic basis of H3.1K27M-induced genomic instability, establishing Arabidopsis as a valuable model for studying processes relevant to plant biotechnology and human health. The findings presented here pave the way for targeted manipulation of DNA integration and identification of potential therapeutic targets for DMG, with applications in genetic engineering, chromatin biology, and cancer research.

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