An organism's genetic information is coded by its DNA sequence, however the activity of genes such as whether they are expressed or silenced, is controlled by "epigenetic marks" on chromatin or modifications of DNA and histones. Epigenetic marks are stable and can be inherited from generation to generation. They also can be disrupted, leading to activation of normally silenced genes and the silencing of normally active genes, the result of which can be developmental abnormalities and other complex diseases. It is well understood that the interactions among DNA, histone proteins and other regulatory factors such as histone modification enzymes, transcription factors, and regulatory noncoding RNAs determine the epigenetic marks including DNA and histone modifications and thus change the 3D packing of nucleosome and gene activities. This project provides new integrated mathematical modeling frameworks for epigenetics to advance our fundamental knowledge on the coupling of the different layers of epigenetics. Researchers involved in the project, including graduate, undergraduate and high school students, will receive solid interdisciplinary training in mathematical modeling of epigenetics-regulated biological systems, including model construction/validation, sensitivity analysis, and deterministic/stochastic simulation.
Noncoding RNAs serve as binding scaffolds for RNA-binding proteins to recruit epigenetic enzymes and thus functions as key regulators that couple epigenetic and genetic regulations. Despite the recognized importance of noncoding RNAs in the regulation of epigenetics, and the abundance of accumulated data in this area, quantitative tools are still lacking to characterize different modes of epigenetic control by noncoding RNAs. The lack of quantitative models of noncoding RNA mediated epigenetic control is largely due to the multiscale coupling of different layers of epigenetics, including histone modification, DNA methylation, and 3D chromosome folding. It is important to determine how these multiscale interactions determine the 3D organization of the chromatin and gene activities. To achieve this goal, a general mathematical framework will be developed to study the nonlinearity of various modes of epigenetic control by noncoding RNAs, and the emergent properties of various recurring regulatory motifs that couples epigenetic and genetic regulation through noncoding RNAs will be investigated. This research will not only provide valuable tools that are currently lacking to dissect the regulation of epigenetics by noncoding RNAs and critical implications for understanding the associated rich nonlinear dynamics and emergent properties, but also lay the foundation for the modeling of a host of biological systems that are regulated by a multiscale epigenetics-genetic regulatory network.
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.
