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MAFA and MAFB contribute to human pancreatic beta cell maturation and function by maintaining histone methylation

Award Number: R03DK149205
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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MAFA and MAFB contribute to human pancreatic beta cell maturation and function by maintaining histone methylation - Abstract Type 2 diabetes (T2D) can be attributed to loss of β cell identity or de-differentiation, marked by acquisition of progenitor cell markers and loss of insulin expression. While the etiology of β cell immaturity in T2D is unclear, impairments in transcription factor (TF) expression occur. My studies will test the hypothesis that the TFs MAF bZIP transcription factor A (MAFA) or B (MAFB) regulate gene expression through interactions with histone modifiers to induce and maintain β cell maturity in humans and that this function is lost during T2D promoting dedifferentiation to a more immature, juvenile state. Preliminary data from bulk RNA-seq of β cell-enriched pseudoislets with knockdown MAFA, MAFB, or both MAFA and MAFB (MAFA/B) found that many of the differentially expressed genes were targets of the PRC2 complex, a histone modifier that tri-methylates histone 3 lysine 27 (H3K27me3) silencing gene expression. Changes in levels of H3K27me3 have been shown in islets from mice fed a high fat diet and in islets from human donors with T2D. H3K27me3 also marks genes in juvenile human islets which are no longer present in genes upregulated in adult islets indicating that PRC2 might be involved in suppressing adult-specific genes to regulate β cell maturation. In addition to PRC-mediated H3K27me3, other histone marks are important for gene regulation in mature adult β cells. At “poised” enhancers, H3K4me1 is present along with H3K27me3; however, in active enhancers H3K27me3 is replaced with H3K27ac. Many β cell-enriched transcription factors (PDX1, NEUROD1, HNF1α/β and HNF4α) have been found to bind the histone acetyltransferases necessary to deposit the H3K27ac mark. Finally, MAFA and MAFB have been shown to specifically interact with MLL3/4 histone modifiers which most frequently leads to the H3K4me1 mark at enhancers. Using β cell-enriched human pseudoislets and EndoC-βH3 cells following loss of MAFA, MAFB, or MAFA/B, I will determine levels of H3K27me3, H3K4me1, and H3K4me3, and H2K27ac by Western blot and immunostaining in human pseudoislets and EndoC-βH3 cells with and without MAFA and/or MAFB. My preliminary data indicates that levels are altered, so I will perform CUT&RUN for these histone marks using β cell-enriched human pseudoislets. I will cross reference these histone modification data with genes differentially expressed in the bulk RNA-seq generated from β cell-enriched pseudoislets with MAFA and/or MAFB knockdown focusing my analysis on previously published developmental and mature gene loci. These DNA-sequencing data will then be compared with that for previously published histone marks from juvenile/adult and T2D islets to determine similarities in pathophysiological states to β cells lacking MAFA and/or MAFB. Finally, I will determine how interactions between methytransferases and MAFA/MAFB are affected by glucolipotoxic conditions and in pancreas sections from pre-diabetic and T2D donors.


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: 2026 ( Subtotal = $116,250 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/19/2026	NEW	$116,250
														Subtotal = $116,250

Grand Total All Awards = $116,250

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MAFA and MAFB contribute to human pancreatic beta cell maturation and function by maintaining histone methylation

Award Number: R03DK149205

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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