Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Lesch, Bluma

Abstract

Histone H3 lysine 4 methylation (H3K4me) is a highly conserved histone post-translational modification linked to active transcription. Although the enzymes that regulate this mark are essential for development, the direct functional role of H3K4me itself remains unclear. To provide a comprehensive overview, I first reviewed evidence from histone residue mutations, histone modifier perturbations, and epigenetic editing studies in yeast, Drosophila, and mammalian systems. This analysis highlights that H3K4me3 instructs transcription initiation and Pol II pause-release at promoters, and H3K4me1 and H3K4me3 may have convergent functions in establishing open chromatin. However, the functional role of H3K4me3 at intergenic site remains poorly understood. To address this gap, I used multi-omics approaches to characterize intergenic H3K4me3, and found that intergenic H3K4me3 is associated with higher transcriptional activity and undergoes active remodeling. Next, I developed a dCas9-based epigenetic editing tool to specifically deposit H3K4me3 at diverse regulatory elements. H3K4me3 at active regulatory element is sufficient to amplify local eRNA transcription, but is not required for enhancer activity. Together, my findings establish a generalizable role for H3K4me3 in reinforcing transcription across the genome and suggest that restricting intergenic H3K4me3 may contribute to transcriptional robustness.

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