Wednesday, September 17, 2025 9/17/2025

Mechanism of yeast gene regulation

Award Number: R35GM131801
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: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Mechanism of yeast gene regulation - PROJECT SUMMARY The mechanisms by which eukaryotes regulate gene expression are important for understanding many complex biological phenomena including human diseases. Prevention and treatment of such diseases have been and will continue to be improved by basic knowledge of gene regulation, especially because molecular mechanisms of transcriptional initiation are highly conserved in eukaryotic organisms ranging from human to yeast. This proposal will continue to investigate basic issues concerning molecular mechanisms of cleavage/ polyadenylation (3’ end formation), and mRNA stability in yeast, by combining molecular genetic, and functional genomic approaches. It will take advantage of our novel methodologies for measuring half-lives, structure (DREADS via chemical probes), protein binding (CLIP-READS), and poly(A) length (A-READS) of individual mRNA 3’ isoforms. Our previous work identified strong and unexpected mechanistic links between transcriptional elongation, cleavage/polyadenylation, and mRNA decay. Novel findings include a nucleotide- level link between elongation and cleavage/polyadenylation, condition-specific 3’ isoform half-lives and mRNA stability elements, and a compensatory mechanism in which the rate of cleavage/polyadenylation in the nucleus is linked to 3’ isoform stability in the cytoplasm. The proposed experiments represent a highly integrated approach to study the generation, structure, stability, and regulation of 3’ isoforms on a transcriptome scale. In addition to our previous experiments that involved relatively stable cytoplasmic mRNAs, the new studies will use a metabolically labeling, pulse-chase approach to analyze newly-synthesized RNAs that are generated in the nucleus prior to transport to the cytoplasm. First, for polyadenylation, we will (A) define the sequence requirements for 3’UTRs by generating large libraries of yeast cells each of which contains a genetically modified 3’UTR, B) use the 3’UTR cell libraries to address the mechanism(s) by which polyadenylation is restricted to the 3' UTR. C) identify factors that are responsible for the wild-type poly(A) pattern, D) determine the mechanistic basis for how individual proteins involved in transcriptional elongation, cleavage/polyadenylation, and mRNA decay affect poly(A) profiles of some genes but not others, and E) elucidate 3'-isoform variation and regulation of poly(A) tail length. Second, for studies of mRNA stabilization/destabilization elements and half-lives of 3' isoforms, we will A) perform RNA structural analysis during the degradation process, B) identify proteins that affect/mediate the large differences in mRNA isoform stabilities C) perform directed genetic experiments to address how secondary structure affects mRNA stability, D) elucidate our recently discovered compensatory mechanism between cleavage/polyadenylation and mRNA decay, E) identify isoform-selective mRNA-binding proteins, and F) investigate the mechanism of condition- specific isoform half-lives and stability elements that we recently identified. Overall, the proposal will answer fundamental questions about the interlinked processes of transcription, polyadenylation, and mRNA stability.


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 = $1,652,828 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	003	7	8/5/2025	NON-COMPETING CONTINUATION	$826,414
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	6	3/24/2025	COMPETING CONTINUATION	$826,414
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	6	3/24/2025	COMPETING CONTINUATION	$22,950
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	6	11/6/2024	COMPETING CONTINUATION	$0
2025	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	5	3/24/2025	NON-COMPETING CONTINUATION	-$22,950
														Subtotal = $1,652,828

Issue Date FY: 2024 ( Subtotal = $826,414 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	6	7/2/2024	COMPETING CONTINUATION	$826,414
2024	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	6/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $826,414

Issue Date FY: 2023 ( Subtotal = $810,210 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	6/14/2023	NON-COMPETING CONTINUATION	$810,210
														Subtotal = $810,210

Issue Date FY: 2022 ( Subtotal = $810,210 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	6/15/2022	NON-COMPETING CONTINUATION	$810,210
														Subtotal = $810,210

Issue Date FY: 2021 ( Subtotal = $810,210 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	6/15/2021	NON-COMPETING CONTINUATION	$810,210
														Subtotal = $810,210

Issue Date FY: 2020 ( Subtotal = $810,210 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	6/10/2020	NON-COMPETING CONTINUATION	$810,210
														Subtotal = $810,210

Issue Date FY: 2019 ( Subtotal = $656,529 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	4/29/2019	NEW	$656,529
														Subtotal = $656,529

Grand Total All Awards = $6,376,611

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Mechanism of yeast gene regulation

Award Number: R35GM131801

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: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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