Dynamic Epigenetic Regulation by Menin During Pancreatic Islet Tumor Formation
Dynamic Epigenetic Regulation by Menin During Pancreatic Islet Tumor Formation
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DOI：
10.1158/1541-7786.mcr-14-0457
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发表时间：
2015-04-01
影响因子：
5.2
通讯作者：
Meyerson, Matthew
中科院分区：
文献类型：
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作者：
Lin, Wenchu;Watanabe, Hideo;Meyerson, Matthew
肿瘤抑制基因MEN1在散发性胰腺神经内分泌肿瘤（PanNET）中经常发生突变，并与家族性多发性内分泌肿瘤1型（MEN1）癌症综合征有关。Menin是MEN1的蛋白产物，在人和小鼠模型系统中与组蛋白甲基转移酶（HMT） MLL1 （KMT2A）和MLL4 （KMT2B）结合形成Menin -HMT复合物。为了阐明menin-HMT复合物介导的赖氨酸4 （H3K4）甲基化在PanNET形成过程中的作用，利用无偏倚染色质免疫沉淀结合下一代测序（ChIP-seq），在胰岛中绘制了全基因组组蛋白H3赖氨酸4三甲基化（H3K4me3）信号。基因表达谱和组蛋白H3K4me3水平的综合分析发现了许多依赖menin的转录本和靶基因。在Men1缺失的情况下，组蛋白H3K27me3水平升高，同时这些靶基因启动子内的H3K4me3水平降低。特别是胰岛素样生长因子2 mRNA结合蛋白2 （IGF2BP2）基因的表达受men1依赖性组蛋白修饰的动态表观遗传调控，且具有时间依赖性。通过消融RBP2 (KDM5A)， IGF2BP2在men1缺陷增生胰岛中的表达降低可以部分逆转，RBP2 （KDM5A）是一种组蛋白h3k4特异性去甲基化酶，属于巨噬细胞，富含at的相互作用结构域1 （JARID1）家族。综上所述，这些数据表明，胰岛细胞中Men1的缺失改变了其靶基因的表观遗传格局。意义：men1缺陷胰岛细胞的表观遗传学分析和基因表达分析揭示了胰岛肿瘤发生过程中发生的分子事件的重要见解。
The tumor suppressor gene MEN1 is frequently mutated in sporadic pancreatic neuroendocrine tumors (PanNET) and is responsible for the familial multiple endocrine neoplasia type 1 (MEN-1) cancer syndrome. Menin, the protein product of MEN1, associates with the histone methyltransferases (HMT) MLL1 (KMT2A) and MLL4 (KMT2B) to form menin-HMT complexes in both human and mouse model systems. To elucidate the role of methylation of histone H3 at lysine 4 (H3K4) mediated by menin-HMT complexes during PanNET formation, genome-wide histone H3 lysine 4 trimethylation (H3K4me3) signals were mapped in pancreatic islets using unbiased chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). Integrative analysis of gene expression profiles and histone H3K4me3 levels identified a number of transcripts and target genes dependent on menin. In the absence of Men1, histone H3K27me3 levels are enriched, with a concomitant decrease in H3K4me3 within the promoters of these target genes. In particular, expression of the insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) gene is subject to dynamic epigenetic regulation by Men1-dependent histone modification in a time-dependent manner. Decreased expression of IGF2BP2 in Men1-deficient hyperplastic pancreatic islets is partially reversed by ablation of RBP2 (KDM5A), a histone H3K4-specific demethylase of the jumonji, AT-rich interactive domain 1 (JARID1) family. Taken together, these data demonstrate that loss of Men1 in pancreatic islet cells alters the epigenetic landscape of its target genes.Implications: Epigenetic profiling and gene expression analysis in Men1-deficient pancreatic islet cells reveals vital insight into the molecular events that occur during the progression of pancreatic islet tumorigenesis.