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Control of gene expression by a metabolite-mRNA interaction network

Award Number: R01CA325384
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Control of gene expression by a metabolite-mRNA interaction network - SUMMARY The regulation of gene expression has long been understood as a process dominated by RNA-binding proteins, microRNAs, or by chemical modifications of RNA itself. Thus, a central dogma in molecular biology is that proteins mediate the interface between cellular metabolism and RNA function. However, our recent work suggests that this view is incomplete: small-molecule metabolites may directly bind to messenger RNAs (mRNAs) and, through this binding, regulate gene expression. Although bacterial riboswitches provide one precedent for this type of regulation, decades of searches have failed to identify similar mechanisms in mammalian cells. This has reinforced the belief that direct metabolite–RNA interactions do not exist in higher organisms. We have developed innovative RNA structure mapping technologies that now make it possible to detect metabolite binding sites with unprecedented resolution. Unlike prior studies that relied solely on in vitro assays, our methods can identify metabolite–RNA interactions in living cells, providing direct evidence that metabolites engage specific mRNAs in physiologic contexts. These approaches allow us to distinguish true binding events from spurious in vitro structural effects and to test whether such interactions influence RNA function. This project will systematically map metabolite–mRNA interactions across the transcriptome, define the mechanisms by which binding alters RNA stability or translation, and establish their physiological roles. We hypothesize that these interactions help maintain metabolic homeostasis by coupling metabolite abundance to the expression of metabolic enzymes, and that ATP–RNA interactions in particular serve as a long-sought retrograde signal linking mitochondrial metabolism to nuclear gene expression. Mechanistically, these interactions may function in unexpected ways: by stabilizing RNA structures, acting as molecular “glues” that recruit proteins, or through other strategies distinct from classical riboswitches. The results will redefine how we think about RNA regulation and metabolism, with implications for diverse fields ranging from RNA biology to cancer metabolism and neurodegeneration. By revealing a direct molecular logic that links metabolite pools to gene expression, this work will provide a web-based resource to access the metabolite-mRNA interaction network, and a new framework that reshapes our understanding of how cells sense and respond to their metabolic environment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,042,140 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	000	1	9/8/2026	NEW	$1,042,140
														Subtotal = $1,042,140

Grand Total All Awards = $1,042,140

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Control of gene expression by a metabolite-mRNA interaction network

Award Number: R01CA325384

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/05/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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