In partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Biology
in the
School of Biological Sciences
Ling Zhu
Will defend her dissertation
Molecular signatures of histone hyperacetylation in embryonic stem cells
Time and Date: 1:30PM (Eastern Time), February 25th, 2025
Location: IBB 2316
Zoom Link: Join Zoom Meeting
Meeting ID: 952 3491 1048
Passcode: 743346
Thesis Advisor:
Yuhong Fan, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Committee Members:
Shuyi Nie, Ph.D.
School of Biological Sciences
Georgia Institute of Technology
Kaixiang Cao, Ph.D.
School of Medicine
Case Western Reserve University
Hengbin Wang, Ph.D.
School of Medicine Internal Medicine
Virginia Commonwealth University
Jiyue Zhu, Ph.D.
School of Pharmacy and Pharmaceutical Sciences
Washington State University
ABSTRACT:
Histone acetylation is a key epigenetic modification that plays a pivotal role in gene expression and stem cell differentiation. This dissertation investigates its regulatory mechanisms by leveraging a genetically encoded histone acetylation biosensor combined with single-cell RNA sequencing of embryonic stem cells (ESCs) and bioinformatics analysis to decipher molecular signatures of histone hyperacetylation in ESCs. Our findings reveal distinct gene expression patterns associated with specific hyperacetylated histones, particularly in genes controlling pluripotency, germ layer formation, development, differentiation, and aging, suggesting histone acetylation plays a crucial role in controlling these processes. Additionally, we examined molecular signatures and the dynamic expression of H1 linker histones in ESCs undergoing histone hyperacetylation induced by acute treatment with the HDAC inhibitor Valproic Acid (VPA). VPA treatment causes histone hyperacetylation and triggers transcriptional signatures indicative of early differentiation and lineage commitment. Quantitative analysis using reverse-phase high performance liquid chromatography and mass spectrometry showed that histone hyperacetylation in ESCs increases total H1 levels and alters H1 variant expression. Further, VPA-induced histone hyperacetylation links to characteristic changes of H1 variants in chromatin, differing from those in embryoid body differentiation, suggesting distinct chromatin remodeling pathways underlying these ESC differentiation processes.
Overall, our results demonstrate that histone hyperacetylation facilitates chromatin remodeling and coordinates with H1 linker histones to regulate transcriptional programs governing stem cell differentiation and fate determination. These molecular signatures highlight its role in chromatin reorganization and gene regulation.