Haberman Nejc, Cheung Rebecca, Pizza Grazia, Cvetesic Nevena, Nagy Dorka, Maude Hannah, Blazquez Lorea, Lenhard Boris, Cebola Inês, Rutter Guy A, Martinez-Sanchez Aida
MRC London Institute of Medical Sciences, London, UK.
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
FASEB J. 2024 Aug 31;38(16):e23885. doi: 10.1096/fj.202401078R.
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-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 β 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 β-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 (TFs) important for β-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 β-cell identity and function.
肝脏激酶B1（LKB1/STK11）是胰腺β细胞特性和功能的重要调节因子。从β细胞中消除Lkb1会导致葡萄糖刺激的胰岛素分泌改善，并伴随着基因表达的深刻变化，包括几个神经元基因的上调。目前，对LKB1控制基因表达的机制了解甚少。在这里，我们探讨了β细胞选择性缺失Lkb1对小鼠胰岛染色质可及性的影响。为了在转录水平上表征LKB1在基因表达调控中的作用，我们将这些数据与胰岛活性转录起始位点和组蛋白标记图谱相结合。我们证明，从β细胞中消除LKB1会导致染色质可及性的广泛变化，这与转录水平的变化相关。数百个启动子和增强子区域发生了变化，其中许多区域靠近神经元基因。我们发现失调的增强子富含对β细胞特性重要的转录因子（TF）的结合基序，如FOXA、MAFA或RFX6，并且我们鉴定了在转录水平上受LKB1调控的微小RNA（miRNA）。总体而言，我们的研究为LKB1调节β细胞特性和功能的表观遗传机制提供了重要的新见解。
