Research Projects

Gene regulation is intricately linked to chromatin structure, specifically through the degree of DNA accessibility controlled by nucleosome unwrapping and rewrapping. The nucleosome, the fundamental unit of chromatin, is composed of DNA wrapped around histone proteins. Among various influencing factors, histone posttranslational modifications (PTMs), like acetylation and phosphorylation, play crucial roles in regulating DNA accessibility. For example, histone acetylation reduces the positive charge of histone tails, promoting DNA accessibility, while phosphorylation contributes to chromatin condensation during cell division. Abnormal PTM patterns are implicated in diseases like cancer, where they may silence tumor suppressor genes or activate oncogenes, and in neurodegenerative disorders by disrupting neuronal function. Despite advancements in experimental methods like single-molecule FRET and cryo-EM, these techniques are limited in capturing fast, dynamic changes across diverse PTM patterns. On the other hand, molecular dynamics (MD) simulations, while powerful for providing atomistic insights, are constrained by the high computational cost required for timescales necessary to observe substantial shifts in nucleosome structure, especially in systems with multiple PTMs. To address these limitations, this project proposes to develop a predictive model integrating equilibrium and non-equilibrium statistical mechanics with PTM-specific parameters, enabling the study of nucleosome unwrapping mechanisms across different PTM configurations. The primary objective is to quantify the influence of histone acetylation and phosphorylation on nucleosome stability and DNA accessibility, focusing on the identification of PTM thresholds that significantly impact nucleosome behavior. The underlying hypothesis is that specific PTM combinations cause distinct structural changes in nucleosomes, directly affecting transcription and linking chromatin structure to disease. This model will integrate MD simulations with equilibrium and non-equilibrium statistical mechanics, providing a new framework for predicting PTM-driven changes in nucleosome structure and accessibility. By offering insights into the molecular basis of chromatin regulation, this research could open avenues for novel therapeutic strategies targeting chromatin dysregulation in disease contexts.