Wednesday, January 15, 2025 1/15/2025

Hematopoietic Regulation via GATA Switches

Award Number: R01DK068634
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Our efforts to forge principles for how GATA factors control development and function of the hematopoietic system led to the discovery of conserved Gata2 enhancers (+9.5 and -77) essential for hematopoiesis and other blood-regulatory enhancers. While genomic studies commonly predict enhancers, there were no reports of enhancers essential for stem cell genesis or progenitor fate decisions. Strikingly, +9.5 mutations resemble GATA2 coding mutations in causing human GATA2-deficiency syndrome involving immunodeficiency, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). -77 disruption also causes MDS/AML. This foundation led clinical centers to analyze -77 and +9.5 genetic variation. We discovered: 1) Whereas +9.5 and -77 confer progenitor cell fate, only +9.5 triggers hematopoietic stem cell genesis. 2) GATA2 loss with EVI1 upregulation is leukemogenic. 3) An ensemble of “+9.5-like” enhancers exist, including one regulating a c-Kit facilitator that promotes erythrocyte regeneration and survival in severe anemia. 4) GATA2-regulated G-protein- coupled receptor circuits control hematopoiesis. 5) We described gain-of-function (GOF) GATA2 mutants, suggesting a paradigm-shift. 6) +9.5 single-nucleotide disease mutation dissociates developmental and regenerative activities, creating a bone marrow failure predisposition. The disease mutations, innovative mouse models, rescue assay and multiomics will enable the following aims. Aim 1 will determine how a blood disease-causing enhancer establishes progenitor cell fate. -77-/- progenitors are defective in erythroid and granulocytic differentiation, yet competent to generate macrophages. Our proteomic and single-cell transcriptome data revealed that skewed differentiation involves upregulated interferon (IFN) response proteins. We hypothesize that convergence of GATA2 and IFN mechanisms is critical in progenitor biology. We will establish the -77-regulated transcriptome/proteome that controls progenitor fate and address key mechanistic issues. Aim 2 will elucidate genetic determinants for the function of essential GATA2 enhancers. We generated compound heterozygous (CH) enhancer mutant mice (-77+/-;+9.5+/-) and discovered that both enhancers must reside on the same allele to regulate progenitor function. We are unaware of any example of a dual enhancer requirement for progenitor function, the mechanisms may inform human +9.5 and -77 enhanceropathies, we will elucidate the mechanisms. Aim 3 will test models for how GATA2 human disease mutants exert gain-of-function activity. We innovated a rigorous rescue assay in which restoring GATA2 in - 77-/- progenitors normalizes skewed differentiation and transcription. Mutants assumed to be loss-of-function (LOF) surprisingly retained activity to rescue granulopoiesis and select target genes. We will test if all disease mutants exhibit GOF activity, elucidate the mechanisms and determine if activities parse mutants into groups that may ultimately inform clinical strategies. These studies will yield basic and translational insights into mechanisms governing GATA factors, hematopoiesis and diverse blood diseases.


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 = $545,540 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	1/8/2025	COMPETING CONTINUATION	$545,540
														Subtotal = $545,540

Issue Date FY: 2024 ( Subtotal = $427,731 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	5/1/2024	NON-COMPETING CONTINUATION	$26,733
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	11/8/2023	NON-COMPETING CONTINUATION	$400,998
														Subtotal = $427,731

Issue Date FY: 2023 ( Subtotal = $445,553 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	1/5/2023	NON-COMPETING CONTINUATION	$44,555
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	12/5/2022	NON-COMPETING CONTINUATION	$400,998
														Subtotal = $445,553

Issue Date FY: 2022 ( Subtotal = $474,897 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	12/8/2021	NON-COMPETING CONTINUATION	$390,179
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	17	2/9/2022	SUPPLEMENT FOR EXPANSION	$11,769
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	17	5/20/2022	SUPPLEMENT FOR EXPANSION	$41,196
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	17	7/13/2022	SUPPLEMENT FOR EXPANSION	-$11,600
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	17	3/29/2022	NON-COMPETING CONTINUATION	$43,353
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	12/3/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $474,897

Issue Date FY: 2021 ( Subtotal = $491,492 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	8/8/2021	COMPETING CONTINUATION	$1,059
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	12/2/2020	COMPETING CONTINUATION	$432,719
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	2/11/2021	SUPPLEMENT FOR EXPANSION	$58,773
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	15	8/8/2021	NON-COMPETING CONTINUATION	-$1,059
														Subtotal = $491,492

Issue Date FY: 2020 ( Subtotal = $340,434 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	2/10/2020	NON-COMPETING CONTINUATION	$340,434
														Subtotal = $340,434

Issue Date FY: 2019 ( Subtotal = $340,434 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/7/2019	NON-COMPETING CONTINUATION	$340,434
														Subtotal = $340,434

Issue Date FY: 2018 ( Subtotal = $340,434 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	1/30/2018	NON-COMPETING CONTINUATION	$306,390
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	4/25/2018	NON-COMPETING CONTINUATION	$34,044
														Subtotal = $340,434

Issue Date FY: 2017 ( Subtotal = $340,434 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	1/24/2017	NON-COMPETING CONTINUATION	$306,390
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	6/15/2017	NON-COMPETING CONTINUATION	$34,044
														Subtotal = $340,434

Issue Date FY: 2016 ( Subtotal = $340,434 )
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	1/20/2016	COMPETING CONTINUATION	$340,434
														Subtotal = $340,434

Issue Date FY: 2015 ( Subtotal = $322,988 )
2015	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	1/15/2015	NON-COMPETING CONTINUATION	$322,988
														Subtotal = $322,988

Issue Date FY: 2014 ( Subtotal = $322,988 )
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	2/25/2014	NON-COMPETING CONTINUATION	$32,299
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	008	9	6/2/2014	NON-COMPETING CONTINUATION	$322,988
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	9	5/29/2014	NON-COMPETING CONTINUATION	-$322,988
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	1/16/2014	NON-COMPETING CONTINUATION	$290,689
2014	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	8	6/2/2014	NON-COMPETING CONTINUATION	$311,684
2014	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	8	5/29/2014	NON-COMPETING CONTINUATION	-$311,684
2014	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	009	7	6/2/2014	NON-COMPETING CONTINUATION	$322,988
2014	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	7	5/29/2014	NON-COMPETING CONTINUATION	-$322,988
2014	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/14/2014	COMPETING CONTINUATION	-$371,250
2014	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	6	5/28/2014	COMPETING CONTINUATION	$371,250
														Subtotal = $322,988

Issue Date FY: 2013 ( Subtotal = $311,684 )
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	1/31/2013	NON-COMPETING CONTINUATION	$290,689
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	5/14/2013	NON-COMPETING CONTINUATION	$20,995
														Subtotal = $311,684

Issue Date FY: 2012 ( Subtotal = $322,988 )
2012	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	2/13/2012	NON-COMPETING CONTINUATION	$322,988
														Subtotal = $322,988

Grand Total All Awards = $6,937,892

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Hematopoietic Regulation via GATA Switches

Award Number: R01DK068634

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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