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A novel link between gene regulation and histone modifications governing islet beta-cell development and function

Award Number: R01DK128132
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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A novel link between gene regulation and histone modifications governing islet beta-cell development and function - ABSTRACT Insulin-secreting b-cells within the pancreatic islets of Langerhans are absolutely required for glucose homeostasis. Loss of b-cell survival or function are hallmarks of type 1 or type 2 diabetes mellitus, respectively, which affects millions of Americans, with numbers expected to greatly increase. This has created enormous economic and health care burdens. Improvements in diabetic therapies will require the deeper understanding of novel mouse and human b-cell regulators and/or pathways directly implicated in b-cell function, including glucose-stimulated insulin secretion (GSIS). The LIM-Homeodomain class transcription factor Islet-1 (Isl1) is an islet-enriched regulator of pancreatic islet cell development, maturation, and function. Despite this, little is known of the transcriptional mechanisms or protein interactors employed by Isl1 to elicit these functions in mouse or human b-cells. To identify components of Isl1 transcriptional complexes, we performed reverse-crosslinked immunoprecipitation and mass spectroscopy experiments using mouse b-cells. We found the novel Isl1 interactors Ring Finger (Rnf)20 and Rnf40, which are E3 ubiquitin ligases that act as a homo- or hetero-dimeric complex to promote transcription via specifically mono-ubiquitinating histone H2B (H2Bub1), a precursor to active histone 3 lysine 4 trimethylation (H34me3). In vitro assays with b-cell lines revealed that (at least) Rnf20 is required for the expression of many Isl1 target genes (e.g., Glut2, MafA, Ins1), as well as GSIS. Strikingly, we also found that reduction of Rnf20 or Isl1 in b-cell lines reduced H2Bub1 and H3K4me3 marks in vitro, thus linking Isl1:Rnf20 to b-cell epigenetics. Our preliminary mouse knockout data support that Rnf20 may act as a homodimer (i.e., without Rnf40) to drive Isl1-mediated target gene regulation in mouse b-cells. Therefore, in this proposal we will compare the functional and transcriptional impacts in mouse models of Isl1 or Rnf20 deficiency, as well as in human b-cells lacking ISL1, RNF20, or RNF40. Our central hypothesis is that b-cell formation and function requires deposition of the H2Bub1 modification by recruited Isl1:Rnf20. We designed three specific aims that will examine the relative functional and gene expression importance of Isl1 and Rnf20 (and thus H2Bub1) in embryonic and adult mouse b-cells, and also in adult human b-cells. Results reported from these studies will establish Rnf20 and the H2Bub1 epigenetic mark as fundamental gene regulatory effectors of Isl1, thus impacting mouse and human b-cell function. Concepts learned will yield new insight into development of novel diabetes drugs or enhance strategies to produce therapeutic b-like cells in vitro.


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 = $502,684 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/29/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$502,684
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	6/26/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$11,930
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	6/26/2025	NON-COMPETING CONTINUATION	-$11,930
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $502,684

Issue Date FY: 2024 ( Subtotal = $438,937 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/3/2024	NON-COMPETING CONTINUATION	$27,434
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/22/2023	NON-COMPETING CONTINUATION	$411,503
														Subtotal = $438,937

Issue Date FY: 2023 ( Subtotal = $457,226 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/9/2023	NON-COMPETING CONTINUATION	$45,723
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/28/2022	NON-COMPETING CONTINUATION	$411,503
														Subtotal = $457,226

Issue Date FY: 2022 ( Subtotal = $458,319 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/30/2021	NEW	$458,319
														Subtotal = $458,319

Grand Total All Awards = $1,857,166

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A novel link between gene regulation and histone modifications governing islet beta-cell development and function

Award Number: R01DK128132

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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