Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells

Haberman, N.; Cheung, R.; Pizza, G.; Cvetesic, N.; Nagy, D.; Maude, H.; Blazquez, L.; Lenhard, B.; Cebola, I.; Rutter, G. A.; Martinez-Sanchez, A.

doi:10.1101/2024.05.13.593867

bioRxiv · 10.1101/2024.05.13.593867

Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells

Haberman, N.·Cheung, R.·Pizza, G.·Cvetesic, N.·Nagy, D.·Maude, H.·Blazquez, L.·Lenhard, B.·Cebola, I.·Rutter, G. A.·Martinez-Sanchez, A.

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Abstract

Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic {beta}-cell identity and function. Elimination of Lkb1 from the {beta}-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of {beta} cell- selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from {beta}-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors important for {beta}-cell identity, such as FOXA, MAFA or RFX6 and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates {beta}-cell identity and function.

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Haberman, N., Cheung, R., Pizza, G., Cvetesic, N., Nagy, D., Maude, H., Blazquez, L., Lenhard, B., Cebola, I., Rutter, G. A., Martinez-Sanchez, A.. 2024-05-15. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. https://doi.org/10.1101/2024.05.13.593867

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