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Mapping the sequence landscape of RNA structure, dynamics and protein interactions using high-throughput single-molecule FRET

Award Number: R35GM147229
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: 09/21/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Mapping the sequence landscape of RNA structure, dynamics and protein interactions using high-throughput single-molecule FRET - Project Summary RNA plays a central role in nearly every biological process, acting in turn as a messenger, catalyst, signaling molecule and more. Many of these roles require RNA to fold into specific structures, and a given RNA species can often adopt multiple structures that modulate properties such as protein interactions, ligand binding and catalytic activity. Research in the Widom Lab focuses on developing and applying new spectroscopic methods to study RNA structure and dynamics. We combine bulk, single-molecule and ultrafast spectroscopy in order to obtain a comprehensive picture of RNA folding and interactions over length-scales from Angstroms to microns and time-scales as short as picoseconds. We are currently using these methods to study RNA-protein interactions during pre-messenger RNA (pre-mRNA) splicing, the process in which segments of RNA that do not code for protein are excised, and ligand binding by riboswitches, which regulate gene expression in bacteria. Single-molecule measurements offer a unique window into the heterogeneous and dynamic nature of RNA folding, and ultrafast spectroscopy probes very rapid processes that are inaccessible by other means. However, these are notably low-throughput techniques, with measurements typically being performed on only a single RNA sequence at a time. An entirely new class of scientific questions could be addressed if these techniques could be applied in a high-throughput manner. We will bring this goal to realization by developing a process for performing single-molecule fluorescence measurements on hundreds of different sequences simultaneously. A library of RNA sequences will be prepared containing random bases at sites of interest and the mixture will be subjected to single-molecule fluorescence measurements to monitor structural rearrangements and response to stimuli in real time. Each molecule will then be sequenced in situ in order to determine what sequence gave rise to its single-molecule signal. Our goals for the next 5 years are to optimize this method and to use it to answer questions that can only be addressed via high-throughput approaches. We will investigate the mechanistic impacts of key sequences on pre-mRNA splicing, including variable sequences that fine-tune splicing and conserved sequences that lead to disease when disrupted. We will also measure the folding thermodynamics and kinetics of hundreds of RNA sequences and use the results to benchmark and improve RNA structure prediction algorithms. This research program will greatly increase the throughput of single-molecule fluorescence measurements, enabling detailed biophysical insights to be achieved rapidly across a vast sequence space.


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 = $362,912 )
2026	2026	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	5	7/10/2026	NON-COMPETING CONTINUATION	$362,912
														Subtotal = $362,912

Issue Date FY: 2025 ( Subtotal = $363,066 )
2025	2025	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	4	8/25/2025	NON-COMPETING CONTINUATION	$363,066
														Subtotal = $363,066

Issue Date FY: 2024 ( Subtotal = $363,215 )
2024	2024	UNIVERSITY OF OREGON	1776 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	3	9/19/2024	NON-COMPETING CONTINUATION	$363,215
														Subtotal = $363,215

Issue Date FY: 2023 ( Subtotal = $363,361 )
2023	2023	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	2	8/7/2023	NON-COMPETING CONTINUATION	$363,361
														Subtotal = $363,361

Issue Date FY: 2022 ( Subtotal = $353,023 )
2022	2022	UNIVERSITY OF OREGON	1585 E 13TH AVE	EUGENE	OR	97403	LANE	USA	Biomedical Research and Research Training	000	1	9/20/2022	NEW	$353,023
														Subtotal = $353,023

Grand Total All Awards = $1,805,577

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Mapping the sequence landscape of RNA structure, dynamics and protein interactions using high-throughput single-molecule FRET

Award Number: R35GM147229

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: 09/21/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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