Doctoral Defense in Biomedical and Health Sciences

On Thursday, 19 June 2025, Juan Ouyang will defend his doctoral thesis in Biomedical and Health Sciences at the Faculty of Medicine, University of Iceland.
The title of the thesis is: Investigating DNA methylation dynamics in normal and epigenetic machinery deficient neurodevelopment.

The opponents are Dr. David Katz, Professor at Emory University in Atlanta, and Dr. Sigríður Rut Franzdóttir, Associate Professor at the Faculty of Life and Environmental Sciences, University of Iceland.

The main supervisor was Professor Hans Tómas Björnsson. Other members of the doctoral committee were Associate Professor Erna Magnúsdóttir, Ólafur Magnússon, group leader at deCODE Genetics, and Professor Ragnhildur Þóra Káradóttir.

Professor Eiríkur Steingrímsson of the Faculty of Medicine will chair the ceremony, which will take place in the Ceremonial Hall (Hátíðasalur) of the University of Iceland and begins at 13:00.

Abstract

Epigenetic machinery (EM) factors are essential for modulating chromatin states and regulating gene expression. The Mendelian disorders of the epigenetic machinery (MDEM), caused by mutations in the EM, often result in shared phenotypes, including intellectual disability and growth dysregulation. Many individuals with an MDEM diagnosis exhibit DNA methylation (DNAm) abnormalities in peripheral blood cells. However, whether DNAm dysregulation in MDEMs functionally links these two overlapping phenotypes remains unclear. This thesis aims to develop a neuronal development model and identify potentially functionally important DNAm loci that show changes across multiple EM deficient neuronal models.
In this study, we successfully established a neuronal development model. We observed extensive global demethylation in Dnmt1KOs, whereas Kmt2aKOs exhibited relatively mild DNAm changes. Additionally, we uncovered a substantial overlap in differentially expressed genes (DEGs), with a strong positive correlation between the shared DEGs among the two.
Beyond individual KO analyses, we systematically investigated DNAm patterns across all 46 EM-KOs. While most exhibited subtle DNAm alterations, notable exceptions included Dnmt1 and Dnmt3b, showed more sizable DNAm changes. Leveraging our experimental setup using cells derived from an F1 hybrid model (B6J paternal × FVB/NJ maternal), we were able to identify allele-specific differentially methylated regions (AS-DMRs) using single-nucleotide polymorphisms (SNPs), and using phasing analysis, we discovered a single genome-wide significant DMR located in the 3´UTR of Zic4, which was differentially expressed during neuronal maturation.
These findings provide a valuable strategy for integrating ONT and RNA sequencing to investigate DNAm dynamics and gene expression changes in a disease-relevant model (neurons). This integrative approach enables the detection of subtle but biologically meaningful candidates that may serve as therapeutic targets or diagnostic markers for MDEMs.

About the doctoral candidate

Juan Ouyang was born in 1997 in China. She completed a BSc degree in bioengineering from Shaoyang University in 2017. She defended her master’s thesis related to epigenetics at Yangzhou University in 2020. Juan then came to Iceland in 2021, when she began her doctoral studies under the supervision of Hans Tómas Björnsson. Her parents are Dalian Ouyang and Xiaoe Wang, both residing in Yiyang, China.