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Predictive understanding of the temporal control of transcription in Drosophila development

Award Number: R01GM139913
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: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Predictive understanding of the temporal control of transcription in Drosophila development - Project Summary/Abstract The correct implementation of developmental programs depends on information encoded in an organism's DNA. Despite decades of work in dissecting the spatial control of gene expression in embryonic development, we know relatively little about the temporal control of these programs—largely due to reliance on dead, fixed tissues. Recently, our lab established new technologies for real-time measurements of input transcription factor concentration dynamics and output transcriptional activity in single cells of the early embryo of the fruit fly Drosophila melanogaster. Our measurements have revealed that the timing of transcription in development is under precise control. Here, we propose a dialogue between theory and experiment to dissect this largely unexplored layer of transcriptional control using the regulation of the hunchback gene by the activator Bicoid and the pioneer-like transcription factor Zelda as a case study. Recent work from our lab has suggested that hunchback transcription ensues as a result of the transition of its promoter through multiple transcriptionally silent states. In this model, Bicoid and Zelda catalyze the transitions between silent states, presumably by triggering the acetylation of nearby histones. In order to systematically test this model of transcriptional onset and reveal the molecular identities of the pathways involved in the dictating transcriptional onset, we will (i) exploit optogenetics to determine whether the timing Bicoid- and Zelda-driven transcriptional onset is independent of the control of mRNA production rates once transcription has already ensued, (ii) harness measurements of the distribution of transcriptional onset times in single cells to uncover the structure of the biochemical cascade leading to transcriptional onset and how this cascade is modulated by Bicoid and Zelda binding, and (iii) identify the histone acetylases and deacetylases invoked by Bicoid and Zelda to dictate transcriptional onset, a process that takes place at time scales that are not accessible by commonplace genome-wide approaches to dissect the chromatin landscape. Overall, our proposed work will establish a clear workflow for the dissection of this new layer of regulatory control given by the timing of transcription in development and for uncovering the underlying molecular pathways. This approach will be amenable to be implemented in other relevant genes in the fruit fly as well as in other workhorses of developmental biology. Further, we envision that our quantitative and predictive approach to dissecting developmental programs will empower future synthetic applications as well as reengineering of multicellular organisms, for example to fix developmental defects or to halt states of unchecked cellular proliferation.


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	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	9/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $298,962 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	4	4/11/2024	NON-COMPETING CONTINUATION	$269,066
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	4	6/18/2024	NON-COMPETING CONTINUATION	$29,896
														Subtotal = $298,962

Issue Date FY: 2023 ( Subtotal = $300,012 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	3	4/26/2023	NON-COMPETING CONTINUATION	$300,012
														Subtotal = $300,012

Issue Date FY: 2022 ( Subtotal = $301,011 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	2	8/3/2022	NON-COMPETING CONTINUATION	$30,101
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	2	4/11/2022	NON-COMPETING CONTINUATION	$270,910
														Subtotal = $301,011

Issue Date FY: 2021 ( Subtotal = $301,962 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	1	7/30/2021	NEW	$301,962
														Subtotal = $301,962

Grand Total All Awards = $1,201,947

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Predictive understanding of the temporal control of transcription in Drosophila development

Award Number: R01GM139913

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: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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