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Transcriptome reprogramming in the early embryo

Award Number: R35GM137973
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: 08/24/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Transcriptome reprogramming in the early embryo - Early in development, a highly coordinated maternal-to-zygotic transition “reprograms” the embryo to a pluripotent cellular identity, capable of giving rise to all subsequent cell types in the developing organism. How cells are induced to pluripotency is still poorly understood, and yet has enormous implications, not only for understanding fundamental developmental and gene regulatory processes, but also for disease modeling and therapies. The long-term goal is to decipher mechanisms and principles conserved across vertebrates that guide pluripotency induction. To begin to address this question, this proposal aims to elucidate how pluripotency factors provided to the egg activate the first genes from the embryonic genome in the model vertebrate zebrafish. Zebrafish produce large clutches of externally developing embryos and express many key regulators of pluripotency that are conserved with humans, making them an ideal experimental system to discover novel regulatory paradigms that induce vertebrate pluripotency. This proposal has three primary goals. First, the regulatory logic underlying the specificity of embryonic gene activation will be deciphered. Maternal pluripotency factors act on a transcriptionally quiescent embryonic genome to initially activate only a few hundred genes, prior to the activation of thousands of genes hours later. Cutting-edge techniques will be used to map pluripotency factor binding genome wide, at earlier developmental stages than have previously been profiled. Binding patterns will be compared in the vicinity of early- versus later activated genes, and distinguishing properties of their respective gene regulatory sequences will be extracted. Second, novel regulators of embryonic genome activation will be deduced by integrating multiple sources of genomics data. These factors will be evaluated using innovative loss-of-function strategies to measure their contributions to embryonic reprogramming and pluripotency. Third, this proposal will uncover post-transcriptional mechanisms that regulate the maternal pluripotency factors themselves. Biochemical and genetic approaches will be used to discover factors that bind maternal mRNA to positively or negatively affect their expression, and in turn exert precise temporal control over pluripotency induction. Together, these analyses will further elucidate the gene regulatory logic of the early vertebrate embryo and provide a deeper understanding of how pluripotent identities are induced.


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 = $425,953 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	6	2/17/2026	COMPETING CONTINUATION	$425,953
2026	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	5	4/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $425,953

Issue Date FY: 2024 ( Subtotal = $363,575 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	7/10/2024	NON-COMPETING CONTINUATION	$363,575
														Subtotal = $363,575

Issue Date FY: 2023 ( Subtotal = $363,575 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	6/27/2023	NON-COMPETING CONTINUATION	$363,575
														Subtotal = $363,575

Issue Date FY: 2022 ( Subtotal = $363,575 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	3	7/29/2022	NON-COMPETING CONTINUATION	$363,575
														Subtotal = $363,575

Issue Date FY: 2021 ( Subtotal = $397,909 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	2	9/17/2021	SUPPLEMENT FOR EXPANSION	$38,745
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	2	7/20/2021	NON-COMPETING CONTINUATION	$359,164
														Subtotal = $397,909

Issue Date FY: 2020 ( Subtotal = $358,763 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	8/24/2020	NEW	$358,763
														Subtotal = $358,763

Grand Total All Awards = $2,273,350

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Transcriptome reprogramming in the early embryo

Award Number: R35GM137973

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: 08/24/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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