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Regulatory elements of replication timing and 3D genome organization

Award Number: R35GM137950
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Regulatory elements of replication timing and 3D genome organization - PROJECT SUMMARY Increasing evidence indicates that three-dimensional (3D) genome organization is required to regulate gene function and its alterations are associated with many diseases. The genome is organized into compartments that align with the temporal order of DNA replication (replication timing – RT). However, little is known about the mechanisms underlying 3D genome organization. Recently, we identified cis elements of RT and 3D genome organization control (early replicating control elements – ERCEs) in murine embryonic stem cells. ERCEs are enriched in enhancer epigenetic marks, form strong chromatin interactions and are bound by pluripotency-specific transcription factors. Moreover, I developed an integrative model of gene regulatory networks that predicts that co-occupancy of cell type-specific transcription factors regulate RT. Here, we will study what are the regulatory elements of genome organization in human differentiated cell types, investigate how trans-acting factors control these elements, and define how 3D genome organization is remodeled during development and evolution. Our central hypothesis is that co-occupancy of cell type-specific transcription factors at ERCEs is required to regulate the 3D genome organization. To test this hypothesis, we will delete and insert candidate ERCEs into the genome of human differentiated cell types and test their effect on RT, 3D genome organization and gene expression. We will track ERCE activation using highly-synchronous human embryonic stem cells differentiation systems. Finally, we will analyze 3D genome organization evolution using primary cells derived from different species. My laboratory is uniquely positioned to perform the proposed research with broad expertise in the experimental design and analysis of 3D genome organization during human cell fate commitment. Moreover, numerous resources available at the University of Minnesota will facilitate the success of this project, including state-of-the-art technologies for genome editing (Genome Engineering Shared Resource), next-generation sequencing (Genomics Center), stem cells (Stem Cell Institute), imaging (Imaging Center) and bioinformatic tools (Minnesota Supercomputing Institute). We expect that our work will contribute significantly to understand the fundamental principles of genome organization and its relationship to gene function. The proposed research combines several innovative aspects such as integrative computational models to predict regulatory elements of large-scale chromatin organization, genome engineering technologies and optimized differentiation protocols of human embryonic stem cells to dissect the mechanisms that control 3D genome organization during development and evolution.


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 MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	5	7/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $386,283 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	5	6/5/2024	NON-COMPETING CONTINUATION	$386,283
														Subtotal = $386,283

Issue Date FY: 2023 ( Subtotal = $584,479 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	5/22/2023	SUPPLEMENT FOR EXPANSION	$10,075
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	002	4	7/3/2023	SUPPLEMENT FOR EXPANSION	$188,121
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	4	6/8/2023	NON-COMPETING CONTINUATION	$386,283
														Subtotal = $584,479

Issue Date FY: 2022 ( Subtotal = $386,288 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	3	6/7/2022	NON-COMPETING CONTINUATION	$386,288
														Subtotal = $386,288

Issue Date FY: 2021 ( Subtotal = $583,996 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	6/8/2021	NON-COMPETING CONTINUATION	$386,570
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	2	9/3/2021	SUPPLEMENT FOR EXPANSION	$197,426
														Subtotal = $583,996

Issue Date FY: 2020 ( Subtotal = $378,043 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	6/29/2020	NEW	$378,043
														Subtotal = $378,043

Grand Total All Awards = $2,319,089

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Regulatory elements of replication timing and 3D genome organization

Award Number: R35GM137950

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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