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.