CAREER: Unraveling the Epigenetic Grammar Governing Chromatin Organization

It is well understood that genetic information encoded in DNA is passed on to future generations. However, genetic information can be modified without altering the DNA sequence, and these modifications can be passed on to future generations. Epigenetics is the study of this processes which shapes the three-dimensional organization of DNA and thus controls gene activity. Dysregulation of epigenetic processes has been implicated in numerous human diseases. Despite decades of research, the precise "epigenetic grammar" -- the rules by which specific combinations of epigenetic modifications collectively shape chromatin structure -- remains elusive. Understanding these molecular mechanisms is critical for advancing fundamental biology and improving the diagnosis and treatment of human diseases. This project will integrate artificial intelligence (AI) with physics-based computational simulations to uncover how epigenetic regulation modulates chromatin structure and function, including its role in the dynamic compartmentalization of DNA within the cell. This project aims to establish detailed molecular links between specific epigenetic modifications and genome function, guiding the rational design of therapeutic strategies targeting epigenetic dysregulation. The tools and methods developed through this project will enable predictive, mechanistic studies of biomolecular assemblies beyond chromatin. The educational activities will launch an AI-visualization suite to engage students from K-12 to graduate levels, both regionally and nationally, in data science, computational modeling, and biomolecular visualization. This project employs a predictive, sequence- and epigenetic-specific simulation model to investigate how epigenetic modifications and regulatory proteins modulate chromatin organization. A central computational challenge in studying epigenetic regulation is the need to simultaneously model large-scale chromatin organization and fine-grained chemical interactions at residue resolution. This project will address this gap by integrating physical modeling with data-driven approaches to build a predictive, residue-level simulation model that quantitatively captures sequence- and epigenetic-specific molecular interactions across hundreds of nucleosomes. Using this model, this project will: (1) Examine key epigenetic modifications -- including acetylation, ubiquitylation, and methylation -- and their interactions with regulatory proteins, focusing on their effects on higher-order chromatin structure and gene regulation; and (2) Elucidate how epigenetic regulation drives chromatin phase separation and governs the biophysical properties of chromatin condensates in the crowded in vivo nuclear environment, as well as how this environment, in turn, modulates biomolecular interactions. By linking chromatin phase separation, epigenetic profiles, and regulatory proteins, this project aims to reconcile different observations of epigenetic effects, decipher the epigenetic grammar underlying chromatin organization, and identify critical chromatin interactions that drive genome compartmentalization. Ultimately, our research will deepen our understanding of genome organization and enhance our ability to evaluate, forecast, and design preventive strategies to mitigate the adverse impacts of epigenetic dysregulation on the genome and epigenome. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540505 | Program: 01003031DB NSF RESEARCH & RELATED ACTIVIT,01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Xingcheng Lin | Institution: North Carolina State University, RALEIGH, NC | Award Amount: $801,725 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540505 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540505.html