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Activity of Estrogen Receptor Enhancers with Chromatin

Award Number: R01DK058110
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2000
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Activity of Estrogen Receptor Enhancers with Chromatin - Cellular signaling by estrogens plays a critical role in the development, physiology, and pathology of a wide variety of tissues, including the reproductive organs, mammary glands, bone, heart, vasculature, adipose, liver, and central nervous system, as well as common diseases of the same tissues. The molecular actions of estrogens are mediated through estrogen receptor proteins (e.g., ERα), which function as transcription factors that drive cell type-specific patterns of gene expression by promoting the coordinated assembly of transcriptional enhancers at ERα binding sites. Studies over the past decade have led to the discovery of short noncoding RNAs that are transcribed by from active enhancers. The functions of these enhancer RNAs (eRNAs) are not well understood, but emerging evidence suggests that eRNAs may contribute to enhancer assembly and function, and target gene expression. These observations have led to a growing interest in the mechanisms and functions of signal-regulated eRNAs, but many questions remain. We still do not know what fraction of eRNAs is functional. In addition, we do not know how eRNAs (1) cooperate with signal-regulated transcription factors, like ERα, and coregulators to regulate enhancer activity, (2) regulate the kinetics of enhancer assembly and disassembly, (3) drive enhancer-promoter looping and the activation of target genes, and (4) regulate mammalian enhancers and gene expression in vivo. The long-term objective of these studies is to better understand the molecular mechanisms of estrogen signaling and gene regulation. Specifically, this proposal focuses on the mechanisms by which eRNAs transcribed from estrogen-regulated enhancers cooperate with liganded ERα to regulate global patterns of gene expression and control biological outcomes. Our broad hypothesis is that eRNAs cooperate with ligand- and DNA-bound ERα to build a scaffold for the assembly of a multi-protein enhancer complex that drives looping to estrogen-regulated target genes, whose expression determines estrogen-dependent biological responses. We propose to explore the mechanisms of eRNA-mediated ER? enhancer assembly and activity, as well as the biological roles of eRNAs in vivo, using an integrated set of experimental approaches. Our specific aims are to: (1) Explore the functional links between estrogen-regulated eRNAs and target gene expression (Aim 1); (2) Determine the molecular mechanisms by which functional estrogen- regulated eRNAs promote enhancer activity (Aim 2); and (3) Identify estrogen-regulated eRNAs in mouse uterus in vivo and perform an initial analysis of their roles in enhancer assembly and function (Aim 3). Our integrative studies on the molecular mechanisms and functions of eRNAs acting at ERα enhancers will elaborate a facet of the estrogen signaling pathway that remains largely unexplored. This knowledge of the molecular actions of estrogens will suggest new ways to prevent, diagnose, and treat estrogen-related diseases. In addition, these studies will shed light on gene regulation by related transcription factors.


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 = $610,113 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	6/16/2025	COMPETING CONTINUATION	$610,113
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	25	7/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $610,113

Issue Date FY: 2024 ( Subtotal = $473,760 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	5/20/2024	NON-COMPETING CONTINUATION	$473,760
														Subtotal = $473,760

Issue Date FY: 2023 ( Subtotal = $499,077 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	7/6/2023	NON-COMPETING CONTINUATION	$499,077
														Subtotal = $499,077

Issue Date FY: 2022 ( Subtotal = $494,895 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	23	5/13/2022	NON-COMPETING CONTINUATION	$494,895
2022	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	10/31/2021	COMPETING CONTINUATION	$61,403
2022	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	10/31/2021	NON-COMPETING CONTINUATION	-$61,403
														Subtotal = $494,895

Issue Date FY: 2021 ( Subtotal = $498,367 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	5/6/2021	COMPETING CONTINUATION	$498,367
														Subtotal = $498,367

Issue Date FY: 2020 ( Subtotal = $444,274 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	5/15/2020	NON-COMPETING CONTINUATION	$444,274
														Subtotal = $444,274

Issue Date FY: 2019 ( Subtotal = $444,274 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	7/11/2019	NON-COMPETING CONTINUATION	$444,274
														Subtotal = $444,274

Issue Date FY: 2018 ( Subtotal = $444,274 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	7/17/2018	NON-COMPETING CONTINUATION	$444,274
														Subtotal = $444,274

Issue Date FY: 2017 ( Subtotal = $455,936 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	7/12/2017	NON-COMPETING CONTINUATION	$455,936
2017	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	1/3/2017	COMPETING CONTINUATION	$79,650
2017	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	1/3/2017	NON-COMPETING CONTINUATION	-$79,650
														Subtotal = $455,936

Issue Date FY: 2016 ( Subtotal = $449,926 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	9/19/2016	COMPETING CONTINUATION	$449,926
2016	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	752359022	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	9/14/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $449,926

Issue Date FY: 2015 ( Subtotal = $396,966 )
2015	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	7/31/2015	NON-COMPETING CONTINUATION	$396,966
														Subtotal = $396,966

Issue Date FY: 2014 ( Subtotal = $396,966 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	7/24/2014	NON-COMPETING CONTINUATION	$396,966
														Subtotal = $396,966

Issue Date FY: 2013 ( Subtotal = $330,739 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	9/5/2013	NON-COMPETING CONTINUATION	$383,072
2013	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	9/3/2013	NON-COMPETING CONTINUATION	-$52,333
														Subtotal = $330,739

Issue Date FY: 2012 ( Subtotal = $545,179 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/20/2012	SUPPLEMENT FOR EXPANSION	$59,173
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	8/22/2012	NON-COMPETING CONTINUATION	$486,006
														Subtotal = $545,179

Issue Date FY: 2011 ( Subtotal = $388,794 )
2011	2011	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	12	9/19/2011	COMPETING CONTINUATION	$387,383
2011	2009	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Trans-NIH Recovery Act Research Support	000	9	4/12/2011	SUPPLEMENT FOR EXPANSION	$0
2011	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	11	6/24/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$49,671
2011	2009	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	6/24/2011	NON-COMPETING CONTINUATION	-$48,260
2011	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	11	9/19/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $388,794

Issue Date FY: 2009 ( Subtotal = $292,742 )
2009	2009	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Trans-NIH Recovery Act Research Support	001	9	9/2/2009	SUPPLEMENT FOR EXPANSION	$7,546
2009	2009	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Trans-NIH Recovery Act Research Support	000	9	7/13/2009	SUPPLEMENT FOR EXPANSION	$8,747
2009	2009	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	10	7/8/2009	NON-COMPETING CONTINUATION	$276,449
														Subtotal = $292,742

Issue Date FY: 2008 ( Subtotal = $277,619 )
2008	2008	CORNELL UNIVERSITY, ENDOWED COLLEGES	EAST HILL PLAZA	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/9/2008	NON-COMPETING CONTINUATION	$277,619
														Subtotal = $277,619

Issue Date FY: 2007 ( Subtotal = $284,420 )
2007	2007	CORNELL UNIVERSITY, ENDOWED COLLEGES	EAST HILL PLAZA	ITHACA	NY	14850	TOMPKINS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/14/2007	NON-COMPETING CONTINUATION	$284,420
														Subtotal = $284,420

Grand Total All Awards = $9,842,215

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Activity of Estrogen Receptor Enhancers with Chromatin

Award Number: R01DK058110

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2000

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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