Saturday, April 20, 2024 4/20/2024

cis-Acting Elements Regulating Developmental Control of Replication Timing

Award Number: R01GM083337
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT DNA replication is central to the structural and functional integrity of the genome and intimately tied to large- scale 3D chromosome organization and cell lineage specification, but we understand little about its regulation. We have identified specific cis-elements, termed Early Replication Control Element (ERCEs), that regulate replication timing (RT), chromosome architecture, and transcription in murine embryonic stem cell (mESCs). ERCEs harbor acetylated histones, form CTCF/cohesin-independent 3D interactions and are co-occupied by pluripotency transcription factors Oct4, Sox2 and Nanog (OSN). What is not known is how these properties control chromosome structure and function and whether their activities are separable. Our long-term goal is to understand the relationship of RT to chromosome architecture, epigenetic states and disease. Our immediate goal is to identify mechanisms by which ERCEs co-regulate RT, chromatin architecture and transcription. Our central hypothesis is that ERCEs interact to create 3D hubs of histone acetylation that recruit replication initiation factors while independently regulating transcription. Our rationale is that elucidating mechanisms by which ERCEs co-regulate RT, transcription and genome architecture will open new horizons for studies of chromosome structure and function and, ultimately, its mis-regulation in disease states. Aim1 will genetically dissect ERCEs to identify minimal sequences necessary and sufficient for their associated activities. Aim2 tests the hypothesis that Rif1, which resides in late replicating chromatin but is necessary RT genome-wide, focuses histone acetylation to ERCEs to recruit the replication initiation protein Treslin through its interaction with histone acetylation binding proteins Brd2 and Brd4. Aim3 will address the longstanding relationship of RT to transcription. We propose that cell type specific transcription factors create hubs of histone acetylation independent of their roles in RT and architecture. This contribution will be significant because it will lift a major barrier to the study of mechanisms regulating chromosome structure and function, how they are regulated during cell fate transitions and, ultimately, how they are mis-regulated in human disease. This work is innovative because the breakthrough discovery of ERCEs introduces novel hypotheses, concepts and approaches to the genome-architecture field.


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: 2023 ( Subtotal = $432,002 )
2023	2023	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	000	16	3/15/2023	NON-COMPETING CONTINUATION	$432,002
2023	2023	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	001	16	6/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $432,002

Issue Date FY: 2022 ( Subtotal = $328,131 )
2022	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	000	15	4/26/2022	NON-COMPETING CONTINUATION	$328,131
														Subtotal = $328,131

Issue Date FY: 2021 ( Subtotal = $275,306 )
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	003	14	7/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$275,306
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	005	14	8/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$44,346
2021	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	13	6/14/2021	COMPETING CONTINUATION	$19,139
2021	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	002	13	7/26/2021	COMPETING CONTINUATION	$0
2021	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	004	13	8/28/2021	COMPETING CONTINUATION	-$44,346
2021	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	12	6/14/2021	NON-COMPETING CONTINUATION	-$19,139
														Subtotal = $275,306

Issue Date FY: 2020 ( Subtotal = $371,574 )
2020	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	13	5/12/2020	COMPETING CONTINUATION	$371,574
2020	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	12	5/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $371,574

Issue Date FY: 2019 ( Subtotal = $326,008 )
2019	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	12	3/20/2019	NON-COMPETING CONTINUATION	$326,008
														Subtotal = $326,008

Issue Date FY: 2018 ( Subtotal = $326,008 )
2018	2018	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	11	2/28/2018	NON-COMPETING CONTINUATION	$293,408
2018	2018	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	11	6/5/2018	NON-COMPETING CONTINUATION	$32,600
														Subtotal = $326,008

Issue Date FY: 2017 ( Subtotal = $327,586 )
2017	2017	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	002	10	6/15/2017	NON-COMPETING CONTINUATION	$32,600
2017	2017	FLORIDA STATE UNIVERSITY, THE	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	10	3/31/2017	NON-COMPETING CONTINUATION	$293,408
2017	2016	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	9	3/28/2017	COMPETING CONTINUATION	$1,578
														Subtotal = $327,586

Issue Date FY: 2016 ( Subtotal = $424,504 )
2016	2016	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	9	8/30/2016	SUPPLEMENT FOR EXPANSION	$69,796
2016	2016	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	9	6/14/2016	COMPETING CONTINUATION	$354,708
														Subtotal = $424,504

Issue Date FY: 2015 ( Subtotal = $296,897 )
2015	2015	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	8	2/6/2015	NON-COMPETING CONTINUATION	$29,689
2015	2015	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	8	12/22/2014	NON-COMPETING CONTINUATION	$267,208
														Subtotal = $296,897

Issue Date FY: 2014 ( Subtotal = $296,897 )
2014	2014	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	7	12/23/2013	NON-COMPETING CONTINUATION	$267,209
2014	2014	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	7	3/10/2014	NON-COMPETING CONTINUATION	$29,688
														Subtotal = $296,897

Issue Date FY: 2013 ( Subtotal = $286,506 )
2013	2013	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	6	12/14/2012	NON-COMPETING CONTINUATION	$267,209
2013	2013	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	6	7/2/2013	NON-COMPETING CONTINUATION	$19,297
														Subtotal = $286,506

Issue Date FY: 2012 ( Subtotal = $296,897 )
2012	2012	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	5	2/13/2012	COMPETING CONTINUATION	$296,897
2012	2010	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	001	4	2/13/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $296,897

Issue Date FY: 2010 ( Subtotal = $273,524 )
2010	2010	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	8/23/2010	NON-COMPETING CONTINUATION	$273,524
														Subtotal = $273,524

Issue Date FY: 2009 ( Subtotal = $386,811 )
2009	2009	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	3	8/5/2009	NON-COMPETING CONTINUATION	$276,561
2009	2009	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Trans-NIH Recovery Act Research Support	001	3	8/31/2009	SUPPLEMENT FOR EXPANSION	$110,250
														Subtotal = $386,811

Issue Date FY: 2008 ( Subtotal = $277,037 )
2008	2008	Florida State University	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	2	8/11/2008	NON-COMPETING CONTINUATION	$277,037
														Subtotal = $277,037

Issue Date FY: 2007 ( Subtotal = $277,037 )
2007	2007	Florida State University	97 S WOODWARD AVE, 3RD FLOOR	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	1	9/21/2007	NEW	$277,037
														Subtotal = $277,037

Grand Total All Awards = $5,202,725

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cis-Acting Elements Regulating Developmental Control of Replication Timing

Award Number: R01GM083337

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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