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The Biophysical and Molecular Mechanisms of Reliability in Development

Award Number: R01GM097275
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: 07/21/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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The Biophysical and Molecular Mechanisms of Reliability in Development - Project Summary Metazoan development relies on precise and reproducible cell fate decisions. However, the molecular events underlying these decisions, namely transcriptional activation of subsets of genes, are inherently stochastic. The goal of the proposed study is to bridge this gap by uncovering how precise patterns emerge from dynamic gene activation. Our past work was mostly focused on the readout of regulatory DNA sequences, such as enhancers, controlling the activation of a target gene. However, during the previous funding cycle, we identified the functional importance of the large chromosomal distances over which this regulation takes place, contributing to often rate- limiting dynamics and adding an extra source for stochasticity. Numerous studies in the past decade have pointed to the prevalence of such long-range chromosomal interactions adding another layer of complexity to the regulation of gene expression. However, investigation of temporal dynamics of chromatin is strongly limited by the prevalent use of bulk assays using fixed material, and traditional imaging methods often lack the spatiotemporal resolution to accurately capture the dynamics of gene activity. Here we propose to overcome these limitations by developing new imaging approaches and computational analyses to provide a dynamic picture of chromosomal architecture and its causal relationship to transcription. For this purpose, we will capitalize on the advantages of the early Drosophila embryo for the development of quantitative live imaging methods. In this system, changes in segmentation gene expression are position-specific determinants of cell- type identity. We will thus examine regulatory interactions at scales characteristic to flies and mammals (from tens to hundreds of kilobases) and their implications in the context of cellular specification in a developing organism. The proposed studies will help understand how robust cell type specification emerges from the stochastic gene expression that is regulated by long-range interactions and chromatin architecture. The following three complementary hypotheses are tested: 1) distinct locus-specific architectures generate different functional outputs; 2) physical order underlies long-distance chromosomal relationships; 3) a functional relationship exists between chromatin dynamics and activity. The overall goal of this project is to establish a quantitative link between chromatin architecture and transcriptional activity, which will ultimately lead us to regulate and re- engineer transcriptional programs underlying development and disease processes.


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	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	14	6/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $380,806 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	14	6/21/2024	NON-COMPETING CONTINUATION	$380,806
														Subtotal = $380,806

Issue Date FY: 2023 ( Subtotal = $380,806 )
2023	2023	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	13	6/27/2023	NON-COMPETING CONTINUATION	$380,806
														Subtotal = $380,806

Issue Date FY: 2022 ( Subtotal = $380,806 )
2022	2022	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	12	6/27/2022	NON-COMPETING CONTINUATION	$380,806
														Subtotal = $380,806

Issue Date FY: 2021 ( Subtotal = $380,806 )
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	11	7/2/2021	NON-COMPETING CONTINUATION	$380,806
														Subtotal = $380,806

Issue Date FY: 2020 ( Subtotal = $407,806 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	10	7/27/2020	COMPETING CONTINUATION	$407,806
2020	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	9	7/1/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $407,806

Issue Date FY: 2019 ( Subtotal = $376,653 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	9	2/18/2019	NON-COMPETING CONTINUATION	$376,653
														Subtotal = $376,653

Issue Date FY: 2018 ( Subtotal = $395,516 )
2018	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	8	3/8/2018	NON-COMPETING CONTINUATION	$355,964
2018	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	8	5/30/2018	NON-COMPETING CONTINUATION	$39,552
														Subtotal = $395,516

Issue Date FY: 2017 ( Subtotal = $396,034 )
2017	2017	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	7	2/13/2017	NON-COMPETING CONTINUATION	$356,431
2017	2017	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	003	7	6/13/2017	NON-COMPETING CONTINUATION	$39,603
2017	2016	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	6	12/17/2016	COMPETING CONTINUATION	$77,385
2017	2015	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	5	12/17/2016	NON-COMPETING CONTINUATION	-$77,385
														Subtotal = $396,034

Issue Date FY: 2016 ( Subtotal = $396,539 )
2016	2016	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	6	7/12/2016	COMPETING CONTINUATION	$396,539
2016	2015	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	085445292	MERCER	USA	Biomedical Research and Research Training	000	5	7/11/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $396,539

Issue Date FY: 2015 ( Subtotal = $287,664 )
2015	2015	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	5	5/15/2015	NON-COMPETING CONTINUATION	$287,664
														Subtotal = $287,664

Issue Date FY: 2014 ( Subtotal = $286,524 )
2014	2014	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	4	5/23/2014	NON-COMPETING CONTINUATION	$286,524
														Subtotal = $286,524

Issue Date FY: 2013 ( Subtotal = $275,397 )
2013	2013	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	3	5/23/2013	NON-COMPETING CONTINUATION	$275,397
														Subtotal = $275,397

Issue Date FY: 2012 ( Subtotal = $262,798 )
2012	2012	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	2	5/9/2012	NON-COMPETING CONTINUATION	$262,798
														Subtotal = $262,798

Issue Date FY: 2011 ( Subtotal = $262,529 )
2011	2011	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	7/18/2011	NEW	$262,529
														Subtotal = $262,529

Grand Total All Awards = $4,870,684

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The Biophysical and Molecular Mechanisms of Reliability in Development

Award Number: R01GM097275

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: 07/21/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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