Dissecting metabolite-mediated gene regulation through dynamic interactions between an enzyme sensor and chromatin modifiers

This project will investigate how small molecules produced in plant cells regulate gene activity. Plants produce a vast diversity of metabolites that are essential for growth, environmental responses, and the synthesis of valuable natural products, but their production must be tightly regulated in cells to avoid wasting energy or overaccumulation of harmful compounds. This research focuses on how small-molecule metabolites trigger feedback regulation of gene expression, a fundamental but poorly understood process in biology. Using petunia flowers as a model system, the project will examine how a metabolic enzyme may act as a sensor that links chemical changes in the cell to chromatin-based gene regulation. The findings will advance our understanding of how metabolism and gene expression are integrated, with broader relevance to plants and other biological systems. The project has potential biotechnology benefits for metabolic engineering and crop improvement by providing new strategies to optimize the production of beneficial natural products and improve plant health. In addition, the project will train postdoctoral researchers and students across multiple levels in interdisciplinary research spanning metabolism, gene regulation, bioinformatics, and biophysics, while engaging the public through outreach on plant chemical diversity. The research will test the hypothesis that a biosynthetic enzyme functions as a sensor that detects metabolite fluctuations and mediates the dynamic behavior of two chromatin modifiers with opposing roles, thereby altering histone acetylation and gene transcription. To address this hypothesis, the project will: (1) characterize the enzymatic activity of the enzyme sensor and determine its interactions with small-molecule metabolites and chromatin regulators; (2) define the spatiotemporal dynamics and nuclear-cytosolic partitioning of chromatin modifying proteins using single-molecule spectroscopy, subcellular fractionation, and phosphoproteomics; and (3) identify the epigenomic and transcriptomic mechanisms underlying feedback inhibition of biosynthetic genes through functional genomics and epigenomics analyses. By uncovering a mechanistic framework for metabolite-mediated chromatin regulation, the project is expected to reveal a novel and generalizable mode of small-molecule-mediated feedback control that links cellular metabolism to transcriptional regulation that have implications for biotechnology and crop improvement. 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: 2545054 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Ying Li | Institution: Purdue University, WEST LAFAYETTE, IN | Award Amount: $1,200,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2545054 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2545054.html