Genetic and Epigenetic Variations
The genome is often hailed as the blueprint of life, but the precise way this blueprint maps into different cell identities remains largely unknown. Both genome and epigenome play a pivotal role in orchestrating this mapping through the intricate control of gene expressions. Their variations, manifested as change of DNA sequences and their post-translational modifications, govern cell identity changes during development, and their dysregulations have been associated with numerous human diseases.
We will develop innovative computational models to characterize genetic and epigenetic variations. Particularly, we will investigate structural changes of chromatin caused by different genetic and epigenetic variations, and their regulation by various epigenetic factors. By combining simulation and data-driven methods, we aim to uncover the “molecular signatures” governing genome and epigenome variations, and determine their impact on regulation of gene expressions.
Molecular Mechanisms of Epigenetic Enzymes
Epigenetic enzymes play a pivotal role in maintaining cell identities by catalyzing and distributing histone modifications, which further regulate chromatin structures. Despite decades of research, the mechanism by which epigenetic enzymes interact with chromatin to orchestrate the delivery of epigenetic signals remains enigmatic.
We will employ simulation and bioinformatics tools to investigate the dynamic interactions between chromatin and their epigenetic “readers” and “writers”. As many epigenetic enzymes have been shown to function through modulating chromatin condensates, we will also explore their role in condensate formation. A complete picture of the interactions between nucleosomes and epigenetic enzymes will provide valuable insights into the molecular mechanisms governing the distribution and inheritance of epigenetic signals. Since dysregulation of epigenetics is associated with numerous human diseases, our research will open a new avenue for developing therapeutic interventions against diseases caused by epigenetic misregulations.
Structure-function Relationship of Noncoding RNAs
Noncoding RNAs (ncRNAs) play a critical role in epigenetic regulation, occupying approximately 70% of the human genome. Recent experimental and computational progress has revolutionized our understanding of these genome “dark matters”. Many ncRNAs, especially long noncoding RNAs (lncRNAs), regulate gene expressions by forming chromatin loops to enhance gene expression, bringing functional proteins into spatial proximity, and recruiting epigenetic enzymes to modulate chromatin structures. Understanding the structure-function relationship of ncRNAs necessitates accurate characterization of protein-RNA interactions.
We will develop innovative models to study the structure and function of ncRNA, as well as their interactions with proteins. Particularly, we will employ simulation to investigate the molecular mechanisms underlying the recruitment of epigenetic enzymes by ncRNAs to regulate gene expressions. Through these efforts, we aim to illustrate the intricate mechanisms behind ncRNA-mediated epigenetic regulation, paving the way for designing therapeutic strategies for treating diseases caused by ncRNA dysregulation.