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Genome-wide Mapping of Ribosome Occupancies with Inhibitor-Induced mRNA Covalent Labeling

Award Number: R21GM148899
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Genome-wide Mapping of Ribosome Occupancies with Inhibitor-Induced mRNA Covalent Labeling - Title: Genome-wide Mapping of Ribosome Occupancies with Inhibitor-Induced mRNA Covalent Labeling Ribosome profiling is a powerful method to study translation through genome-wide mapping of translating ribosomes. This breakthrough technology has illuminated many facets of protein synthesis, such as ribosomal pausing, alternative initiation sites, and protein synthesis rates across numerous cellular systems. Although recent innovations have reduced ribosome profiling to single cells, ribosome profiling typically requires large numbers of cells to conduct and therefore is not routinely used to study rare cell types and clinical samples. Furthermore, ribosome profiling fragments mRNA and hence cannot map multiple ribosomes along a single mRNA molecule and requires integration of separate mRNA sequencing datasets to account for the total number of transcripts. New efficient methods to simultaneously measure ribosome occupancies and mRNA abundance by preserving mRNA integrity would further enable the global study of translational regulation and provide new fundamental insight into translation dynamics. To bridge these technological gaps, here we propose to develop new small molecule tools based off the natural product ribosome inhibitors to chemically footprint ribosome positioning atop mRNA transcripts through covalent labeling. Our central hypothesis is that these mRNA chemical footprints can be detected through error prone reverse transcription and subsequent mRNA sequencing to map ribosome occupancies while maintaining the integrity of the mRNA. This approach is termed ribosome mutational profiling (Ribo-MaP). To develop Ribo-MaP, the first aim proposes the structure-based design of natural product derivatives that potently inhibit ribosome elongation while maintaining polysome stability. Critically, these derivatives are based off emetine, a ribosome inhibitor which contacts the mRNA template to block translation. Furthermore, photoaffinity labeling groups will be attached to these emetine derivatives and the ability to covalently label mRNA will be tested. Additionally, an alternative approach for mRNA covalent labeling is proposed, in which emetine derivatives will be functionalized with reactive acylating groups to label the proximal mRNA 2'- hydroxyl. In both approaches, mRNA labeling efficiency and the ability to readout covalent modifications as mutations in error prone reverse transcription will be measured. In the second aim, the ability of Ribo-MaP to map ribosome occupancies genome-wide will be evaluated and benchmarked against conventional ribosome profiling. We expect that Ribo-MaP will bypass inefficient steps in ribosome profiling and drop into the streamlined workflow of both robust mRNA sequencing methods and new emerging technologies for single-cell and long-read mRNA sequencing. Altogether, Ribo-MaP would provide a highly enabling method to broadly study protein synthesis and ribosome dynamics in cells.


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: 2025 ( Subtotal = $0 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	5/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $240,336 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	8/5/2024	NON-COMPETING CONTINUATION	$24,033
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	1/8/2024	NON-COMPETING CONTINUATION	$216,303
														Subtotal = $240,336

Issue Date FY: 2023 ( Subtotal = $198,470 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	1/13/2023	NEW	$198,470
														Subtotal = $198,470

Grand Total All Awards = $438,806

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Genome-wide Mapping of Ribosome Occupancies with Inhibitor-Induced mRNA Covalent Labeling

Award Number: R21GM148899

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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