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Riboswitches and their application to RNA visualization and transcription factor interactions with the transcriptome

Award Number: R35GM152029
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Riboswitches and their application to RNA visualization and transcription factor interactions with the transcriptome - Project Summary A broadly distributed means of bacterial gene regulation is an mRNA element called a riboswitch. These cis-acting elements are found in the 5′-leader regions and regulate expression through their ability to directly bind a specific cellular metabolite with a highly structured receptor called the aptamer domain. Metabolite binding is then communicated to a downstream secondary structural switch in the expression platform that instructs the expression machinery. Genes that are essential for survival or virulence are regulated by riboswitches in numerous medically important pathogens, making riboswitches attractive and novel targets for antimicrobial therapeutics. A long-term goal of my Research Program is to develop a molecular understanding of how mRNA interacts with small molecules and how these interactions drive biological processes. These overarching questions include: (1) How does RNA create small molecule binding pockets that recognize a spectrum of compounds with high affinity and varying degrees of specificity? (2) How can structural plasticity be exploited to by RNA-targeting compounds? (3) What are the mechanisms by which ligand binding drive changes in RNA structure to effect gene regulation? To address these questions, we will use a combination of structural, biophysical, and biochemical approaches as well as in vitro and cell-based functional assays. As our Research Program has developed a detailed understanding of RNA-small molecule interactions, we have begun to leverage this knowledge towards the design of research tools that facilitate basic research and therapeutic application. In this proposal, we are developing novel platforms for tagging RNAs with fluorophores for imaging in live mammalian cells, removing a technical barrier that has limited the study of RNA function. Specifically, we hypothesize that the robust folding and ligand binding properties of riboswitch aptamer domains will provide superior imaging performance over in vitro selected aptamers in cells. Thus, we are developing a set of riboswitch-based tags that bind modular chemical probes and a set of approaches to assess and benchmark their performance in mammalian cells. Recently, we launched a new direction in our Research Program to investigate how classical transcription factors (TFs) interact with the transcriptome as part of their regulatory function. We demonstrated that Sox2, a pioneer TF critical for maintenance of pluripotency and neural differentiation, directly interacts with RNA in mouse embryonic stem cells and binds various RNAs in vitro with affinities that rival its consensus DNA promoter site. We observed similar RNA interactions for other Sox and TCF/LEF family proteins, suggesting that RNA binding may be a general property of HMGB proteins that is critically linked to their function. In this proposal, we seek to extend these initial findings to address a set of key questions: (1) What is the full spectrum of RNAs bound by Sox2? (2) How does RNA binding impact chromosomal localization? (3) What is the structural basis for RNA recognition by HMGB proteins?


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 = $537,668 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	000	3	2/2/2026	NON-COMPETING CONTINUATION	$537,668
														Subtotal = $537,668

Issue Date FY: 2025 ( Subtotal = $597,408 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	2	5/22/2025	NON-COMPETING CONTINUATION	$597,408
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	1	11/25/2024	NEW	$0
														Subtotal = $597,408

Issue Date FY: 2024 ( Subtotal = $597,408 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	1	2/28/2024	NEW	$597,408
														Subtotal = $597,408

Grand Total All Awards = $1,732,484

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Riboswitches and their application to RNA visualization and transcription factor interactions with the transcriptome

Award Number: R35GM152029

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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