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Understanding the role of cell-cycle specific RNAs in hematopoiesis

Award Number: R01DK136116
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: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Understanding the role of cell-cycle specific RNAs in hematopoiesis - (PLEASE KEEP IN WORD, DO NOT PDF) Misregulation of hematopoietic genes can result in disruption of the production of functionally specialized blood cells. Abnormal DNA methylation, a key epigenetic signature essential in hematopoiesis, is regarded as the hallmark of most hematological malignancies, including myelodysplastic syndromes (MDS). Unfortunately, the currently approved demethylating agents act indiscriminately on the entire genome and come with a toll of high toxicity and low specificity. Strategies to achieve selective demethylation are therefore needed. The long-term goal of our research is to understand how to develop a highly specific and low toxic approach to correct aberrant DNA methylation in disease states. The central hypothesis is that the establishment of DNA methylation in hematopoiesis is controlled by specialized RNAs, able to bind to the DNA methyltransferase 1 (DNMT1) – DNMT1- interacting RNAs (DiRs). DiRs are widespread and prevent DNA methylation and silencing in a locus-specific manner. Specifically, we have shown that the expression of a master regulator of hematopoietic differentiation, CCAAT/enhancer-binding protein alpha (CEBPA), is regulated by a DiR originated upstream of the CEBPA gene during the S phase, termed extra-coding (ec)CEBPA. The overall objectives of this proposal are to investigate how ecCEBPA and lineage specific DiRs guide hematopoietic differentiation. The rationale for this project is to demonstrate DiR-mediated regulation of DNA methylation in hematopoiesis. The central hypothesis will be tested by pursuing two specific aims: 1) Define the biological role of ecCEBPA in hematopoietic differentiation; and 2) Define the biological role of DNMT1-interacting RNAs in hematopoietic differentiation. The proposed research is innovative because we will dissect the regulation of DNA methylation in hematopoietic differentiation and uncover the mechanisms underlying the control of cell type-specific methylation patterns. It is significant because we will identify key epigenetic regulators governing the establishment of DNA methylation in hematopoiesis; and lay the foundation for a transformative approach to achieve gene-specific control of this critical epigenetic mark.


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 = $345,800 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/20/2025	NON-COMPETING CONTINUATION	$345,800
														Subtotal = $345,800

Issue Date FY: 2024 ( Subtotal = $331,968 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/12/2024	NON-COMPETING CONTINUATION	$331,968
														Subtotal = $331,968

Issue Date FY: 2023 ( Subtotal = $345,800 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/30/2023	NON-COMPETING CONTINUATION	$345,800
														Subtotal = $345,800

Issue Date FY: 2022 ( Subtotal = $345,800 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/9/2022	NEW	$345,800
														Subtotal = $345,800

Grand Total All Awards = $1,369,368

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Understanding the role of cell-cycle specific RNAs in hematopoiesis

Award Number: R01DK136116

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: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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