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Transcriptional Control of Hemoglobin Synthesis and Erythrocyte Development

Award Number: R01DK050107
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: 07/16/1996
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Transcriptional Control of Hemoglobin Synthesis and Erythrocyte Development - PROJECT SUMMARY Hemoglobin synthesis and erythrocyte development are often studied independently, yet their mechanisms are inextricably linked. Differentiation defects yield immature precursors, and impaired hemoglobin synthesis causes ineffective erythropoiesis. A common thread of these mechanisms is GATA transcription factor involvement. Many questions remain regarding how GATA factor networks instruct progenitors to generate vast numbers of erythrocytes, which broadly informs molecular/cellular biology and hematology. We discovered: 1) locus-specific coregulator utilization by GATA1 to control differentiation; 2) GATA factor/regeneration-activated enhancer confers expression of an unstudied sterile alpha motif domain protein that controls erythrocyte regeneration; 3) GATA factor-regulated zinc transporter switch governs differentiation; 4) mechanism of heme targeting chromatin genome-wide; 5) GATA factor-regulated solute carrier protein (SLC) cohort transports diverse small molecules to control erythropoiesis. Our multi-omic work supports the aims to analyze how GATA factors establish small molecule ensembles that target the genome and regulate the GATA factor to ensure differentiation. Aim 1 will dissect a multi-component mechanism by which GATA1 and heme control genome function and erythrocyte development. GATA1 activates genes mediating heme biosynthesis, heme facilitates or restricts GATA1 function and heme downregulates GATA1. Heme regulates transcription by downregulating the repressor Bach1, and we discovered a Bach1-independent heme-regulated mechanism. We hypothesize that Bach1-dependent and -independent mechanisms establish critical erythroid functions, and these mechanisms provide translational opportunities. Using all heme target genes and a gene-specific approach, we will establish the mechanisms. Aim 2 will elucidate a GATA factor-dependent small molecule transporter axis that regulates erythroid differentiation. We hypothesize that diverse small molecules function in GATA factor mechanisms and discovering GATA factor-regulated solute carrier (Slc) transporters will unveil new dimensions to these mechanisms. We defined a GATA1/2-regulated Slc cohort that transports diverse small molecules. We prioritized a subset with GATA factor-occupied predicted enhancers and will elucidate mechanisms that link GATA factors with small molecule ensembles and differentiation. Aim 3 will test models for how GATA1 instigates a sphingolipid-dependent regulatory network. GATA1-regulated Slcs included sphingolipid transporters. Lipidomics revealed GATA1-induced sphingolipid remodeling. Ceramide synthase inhibition blocks GATA1-mediated GATA2 downregulation, β-globin induction and erythroid maturation. Sphingolipid signaling controls apoptosis, proliferation and migration, high S1P is deleterious in sickle cell disease, and human ceramide deficiency involves disrupted erythropoiesis. We hypothesize that sphingolipidome regulation by GATA1 is vital in biology and pathology. We will develop basic and translational insights into GATA factor mechanisms governing small molecules that control GATA factors, globin synthesis and differentiation.


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 = $478,444 )
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	29	5/30/2025	NON-COMPETING CONTINUATION	$478,444
														Subtotal = $478,444

Issue Date FY: 2024 ( Subtotal = $459,306 )
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	28	6/11/2024	NON-COMPETING CONTINUATION	$459,306
														Subtotal = $459,306

Issue Date FY: 2023 ( Subtotal = $478,444 )
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	27	5/23/2023	NON-COMPETING CONTINUATION	$478,444
														Subtotal = $478,444

Issue Date FY: 2022 ( Subtotal = $478,453 )
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	26	5/24/2022	NON-COMPETING CONTINUATION	$478,444
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	3/25/2022	COMPETING CONTINUATION	$9
														Subtotal = $478,453

Issue Date FY: 2021 ( Subtotal = $478,444 )
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	25	8/2/2021	COMPETING CONTINUATION	$0
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	25	7/16/2021	COMPETING CONTINUATION	$478,444
														Subtotal = $478,444

Issue Date FY: 2010 ( Subtotal = $380,805 )
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	9/6/2010	NON-COMPETING CONTINUATION	$281,539
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Trans-NIH Recovery Act Research Support	000	13	1/18/2010	SUPPLEMENT FOR EXPANSION	$99,266
														Subtotal = $380,805

Issue Date FY: 2009 ( Subtotal = $284,453 )
2009	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	7/28/2009	NON-COMPETING CONTINUATION	$284,453
														Subtotal = $284,453

Issue Date FY: 2008 ( Subtotal = $284,521 )
2008	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	12	7/28/2008	NON-COMPETING CONTINUATION	$284,521
														Subtotal = $284,521

Issue Date FY: 2007 ( Subtotal = $295,321 )
2007	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	11	7/11/2007	NON-COMPETING CONTINUATION	$295,321
														Subtotal = $295,321

Issue Date FY: 2006 ( Subtotal = $300,250 )
2006	2006	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	10	8/10/2006	COMPETING CONTINUATION	$300,250
														Subtotal = $300,250

Issue Date FY: 2005 ( Subtotal = $254,235 )
2005	2005	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	9	2/1/2005	NON-COMPETING CONTINUATION	$254,235
														Subtotal = $254,235

Issue Date FY: 2004 ( Subtotal = $254,235 )
2004	2004	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	8	1/19/2004	NON-COMPETING CONTINUATION	$254,235
														Subtotal = $254,235

Issue Date FY: 2003 ( Subtotal = $353,696 )
2003	2003	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	7		NON-COMPETING CONTINUATION	$254,235
2003	2003	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	001	7	9/11/2003	SUPPLEMENT FOR EXPANSION	$99,461
														Subtotal = $353,696

Issue Date FY: 2002 ( Subtotal = $314,122 )
2002	2002	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	001	6	3/13/2002	SUPPLEMENT FOR EXPANSION	$81,044
2002	2002	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	6	12/21/2001	NON-COMPETING CONTINUATION	$233,078
														Subtotal = $314,122

Issue Date FY: 2001 ( Subtotal = $229,224 )
2001	2001	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	001	5	6/12/2001	SUPPLEMENT FOR EXPANSION	$5,396
2001	2001	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	5	2/7/2001	COMPETING CONTINUATION	$223,828
														Subtotal = $229,224

Issue Date FY: 1999 ( Subtotal = $136,347 )
1999	1999	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	4	6/10/1999	NON-COMPETING CONTINUATION	$136,347
														Subtotal = $136,347

Issue Date FY: 1998 ( Subtotal = $131,101 )
1998	1998	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Kidney Diseases, Urology and Hematology Research	000	3	8/25/1998	NON-COMPETING CONTINUATION	$131,101
														Subtotal = $131,101

Grand Total All Awards = $5,591,401

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Transcriptional Control of Hemoglobin Synthesis and Erythrocyte Development

Award Number: R01DK050107

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: 07/16/1996

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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