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Nuclear Pore Complexes As Scaffolds For Genome Architecture And Epigenetic Maintenance

Award Number: R01GM124143
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: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Nuclear Pore Complexes As Scaffolds For Genome Architecture And Epigenetic Maintenance - The Nuclear Pore Complex (NPC) is a nuclear envelope embedded multi-component complex, which mediates transport of molecules between the nucleus and the cytoplasm. In addition to their classical function in transport, NPC components (Nups) have been implicated in transcriptional regulation via binding to the genome. Yet what regulatory steps of transcription are controlled by Nups and how chromatin-binding roles of Nups contribute to metazoan development is currently unclear. We identified the binding of multiple Nups to hundreds of promoters and enhancers in the Drosophila genome, and discovered a previously unreported role of the NPC in the formation of enhancer-promoter loops. Specifically, we identified Nup98 to be required for the formation of an enhancer-promoter loop at a gene activated by a developmental hormone ecdysone. Functionally, we found that the loss of Nup98-mediated enhancer-promoter loop affected the primed response to subsequent activation or transcriptional memory. Interestingly, ecdysone-regulated genes stably associated with nuclear pores before and after activation, suggesting that metazoan NPCs can be utilized as an organizing scaffold for genes awaiting future activation events. Together, these findings implicate Nups as a new class of architectural proteins for enhancers and suggest that stabilization of enhancer-promoter loops by nuclear pore binding constitutes a mechanism of epigenetic maintenance. We project that this function of the nuclear pore will be highly relevant to gene regulation during metazoan development. To be able to investigate the genome- organizing role of Nups in developmental gene regulation, we first plan to identify molecular determinants of Nup-mediated enhancer-promoter looping. Thus, in Aim 1, we will define which Nups and which other architectural proteins participate in the establishment of ecdysone- induced genomic loops. Additionally, we plan to identify DNA elements that are sufficient to tether to the NPC or that are necessary for loop stabilization. In Aim 2, we propose to define the relationship between formation of Nup-mediated enhancer-promoter loops and transcriptional activation and memory, by identifying chromatin changes that occur as a specific consequence of looping. Furthermore, we will examine the effect of Nups on maintenance of genomic loops in fly tissues during development and identify a comprehensive set of genomic contacts that are regulated by Nups. Together, these experiments are expected to expand our knowledge of the driving forces and principles of genome architecture, gene expression and nuclear pore biology.


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 = $325,532 )
2025	2025	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	9	8/19/2025	NON-COMPETING CONTINUATION	$325,532
														Subtotal = $325,532

Issue Date FY: 2024 ( Subtotal = $325,532 )
2024	2024	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	6/14/2024	NON-COMPETING CONTINUATION	$325,532
														Subtotal = $325,532

Issue Date FY: 2023 ( Subtotal = $325,532 )
2023	2023	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	001	7	7/13/2023	NON-COMPETING CONTINUATION	$325,532
2023	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	6/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $325,532

Issue Date FY: 2022 ( Subtotal = $325,532 )
2022	2022	SAN DIEGO STATE UNIVERSITY FOUNDATION	5250 CAMPANILE DR MC1947	SAN DIEGO	CA	92182	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	9/9/2022	COMPETING CONTINUATION	$325,532
														Subtotal = $325,532

Issue Date FY: 2021 ( Subtotal = $338,100 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	8/4/2021	NON-COMPETING CONTINUATION	$338,100
														Subtotal = $338,100

Issue Date FY: 2020 ( Subtotal = $338,100 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	8/28/2020	NON-COMPETING CONTINUATION	$338,100
														Subtotal = $338,100

Issue Date FY: 2019 ( Subtotal = $338,100 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	8/29/2019	NON-COMPETING CONTINUATION	$338,100
														Subtotal = $338,100

Issue Date FY: 2018 ( Subtotal = $338,100 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	8/31/2018	NON-COMPETING CONTINUATION	$338,100
														Subtotal = $338,100

Issue Date FY: 2017 ( Subtotal = $338,100 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	8/30/2017	NEW	$338,100
														Subtotal = $338,100

Grand Total All Awards = $2,992,628

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Nuclear Pore Complexes As Scaffolds For Genome Architecture And Epigenetic Maintenance

Award Number: R01GM124143

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: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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