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Control of precisely timed gene expression during notochord development by Brachyury

Award Number: R01GM149841
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: 07/05/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Control of precisely timed gene expression during notochord development by Brachyury - PROJECT SUMMARY/ABSTRACT Precise temporal regulation of stage-specific gene expression is fundamental for the proper development of all organisms. Different molecular mechanisms that ensure the regionalized activation of gene expression, such as activator gradients or localized transcriptional repressors, have been elucidated in remarkable detail; however, the structural features of cis-regulatory sequences that enable transcription factors to achieve the timely deployment of their downstream genes remain mostly unclear. The evolutionarily conserved transcription factor Brachyury provides an example of a regulator that controls the spatial and temporal expression of a large number of genes, many of which are required for the development of the notochord. The notochord is the main feature shared by all chordate embryos, from tunicates to humans. During the early embryogenesis of all chordates, the notochord provides support and patterning signals to the developing body and is indispensable for patterning neural tube, endoderm, paraxial mesoderm, and the structures that they will form. In the tunicate Ciona, an invertebrate chordate, Brachyury is exclusively expressed in notochord cells, where it controls the expression of hundreds of genes. Even though Ciona Brachyury (Ci-Bra) is steadily transcribed and transported to the nuclei of the notochord cells throughout development, the genes downstream of Ci-Bra exhibit a distinctive, temporally staggered onset. In an effort to identify the cis-regulatory strategies responsible for the precise temporal regulation of notochord gene expression by Ci-Bra, we have characterized several cis-regulatory regions (aka enhancers) that control the notochord expression of Ci-Bra- downstream genes characterized by different temporal onsets. These studies have led us to formulate a working hypothesis that explains how Brachyury controls its early-, middle- and late-onset target genes. This hypothesis will be tested through the following experimental approaches: the elucidation of the cis-regulatory principles underlying the sequential activation of early-onset and middle-onset notochord genes directly controlled by Ci-Bra (Aim 1); the functional analysis of two transcription factors that activate expression of late- onset notochord genes (Aim 2); the exploration of the role of transcriptional repressors in notochord development (Aim 3). These studies will shed light on the modalities employed by a pivotal transcription factor to set the temporal context for developmental processes of widespread relevance, such as convergent extension and extracellular matrix secretion, and will provide the mechanistic framework that is needed to diagnose and prevent malformations and tumorigenesis associated with the multifaceted transcription factor Brachyury.


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 = $322,000 )
2026	2026	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	3	5/20/2026	NON-COMPETING CONTINUATION	$322,000
														Subtotal = $322,000

Issue Date FY: 2025 ( Subtotal = $322,000 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	5/5/2025	NON-COMPETING CONTINUATION	$322,000
														Subtotal = $322,000

Issue Date FY: 2024 ( Subtotal = $322,000 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	7/5/2024	NEW	$322,000
														Subtotal = $322,000

Grand Total All Awards = $966,000

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Control of precisely timed gene expression during notochord development by Brachyury

Award Number: R01GM149841

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: 07/05/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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