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Pioneer factor activity in transcription and DNA replication

Award Number: R35GM148241
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: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Pioneer factor activity in transcription and DNA replication - PROJECT SUMMARY Shortly after fertilization, a dramatic reprogramming of the genome and transcriptome occurs, enabling the embryo to develop quickly and robustly. This is especially exemplified in the Drosophila embryo, which within a two-hour period undergoes 13 mitotic cycles, cellularizes the blastoderm, patterns the body plan, and gets ready for gastrulation. While the gene networks underlying these processes have been well studied, it is not clear how they are collectively initiated, a process referred to as zygotic genome activation. Moreover, although it was observed that DNA replication occurs before transcription, the mechanisms that control this timing are not known. Previously, we demonstrated that a single factor, Zelda, acts globally to activate early-expressed genes. We found that Zelda binding to CAGGTAG sites across the genome lowers nucleosome barriers at enhancers, thereby facilitating the binding of other key transcription factors. Zelda and these other factors are present in sub-nuclear “hubs” (discrete foci) that were seen to colocalize at enhancers. We aim to use high-resolution microscopy to investigate the which structural features of Zelda mediate hub formation. In addition, we are interested in the regulatory mechanisms that control the timing of transcription and DNA replication so that conflicts between the two processes are avoided. We propose that Zelda plays a dual pioneering role: 1) to open chromatin for the Origin Recognition Complex to load and subsequent formation of the Pre-replication Complex, which occludes the transcriptional machinery until origins have fired, and 2) to open newly formed chromatin for transcription to initiate. Our goal is to first define origins of replication in early embryos, and to characterize Zelda's role in origin licensing and transcriptional initiation. Our studies will lend into how these two fundamental processes of DNA replication and transcription are coordinated during genome activation.


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 = $408,370 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	3	12/4/2024	NON-COMPETING CONTINUATION	$352,908
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	3	12/5/2024	SUPPLEMENT FOR EXPANSION	$16,250
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	003	3	8/6/2025	NON-COMPETING CONTINUATION	$39,212
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	11/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $408,370

Issue Date FY: 2024 ( Subtotal = $427,983 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	2	6/24/2024	NON-COMPETING CONTINUATION	$39,831
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	2	11/22/2023	SUPPLEMENT FOR EXPANSION	$29,680
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	11/21/2023	NON-COMPETING CONTINUATION	$358,472
														Subtotal = $427,983

Issue Date FY: 2023 ( Subtotal = $409,219 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	1	8/4/2023	SUPPLEMENT FOR EXPANSION	$11,605
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	12/29/2022	NEW	$397,614
														Subtotal = $409,219

Grand Total All Awards = $1,245,572

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Pioneer factor activity in transcription and DNA replication

Award Number: R35GM148241

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: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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