Abstract
<div>Abstract<p>The tumor suppressor gene <i>MEN1</i> 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 <i>MEN1</i>, 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 <i>Men1</i>, 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 (<i>IGF2BP2</i>) gene is subject to dynamic epigenetic regulation by <i>Men1</i>-dependent histone modification in a time-dependent manner. Decreased expression of <i>IGF2BP2</i> in <i>Men1</i>-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 <i>Men1</i> in pancreatic islet cells alters the epigenetic landscape of its target genes.</p><p><b>Implications:</b> Epigenetic profiling and gene expression analysis in <i>Men1</i>-deficient pancreatic islet cells reveals vital insight into the molecular events that occur during the progression of pancreatic islet tumorigenesis. <i>Mol Cancer Res; 13(4); 689–98. ©2014 AACR</i>.</p></div>
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