Abstract
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. 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.
Highlights
Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant syndrome, characterized by multiple tumors in endocrine tissues such as the pituitary gland, parathyroid gland, and pancreatic islets [1]
To investigate tumor formation mediated by alterations in H3K4me3 levels and to identify gene targets of menin–histone methyltransferases (HMT) complexes, we conducted epigenetic profiling of Men1-deficent pancreatic islets in 2-month-old Men1 conditional knockout mice and control wild-type littermates, Using ChIP techniques coupled with next-generation sequencing (ChIP-seq), we found that Men1 loss lowered H3K4me3 levels at select target gene promoters, resulting in downregulation of gene expression
Our finding is consistent with earlier studies demonstrating that in contrast to Set1a and Set1b, the major H3K4 trimethylases in mammalian cells [30], MLL1 and MLL4, the HMTs known to associate with menin, are responsible for H3K4 trimethylation of only a subset of loci [31]
Summary
Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant syndrome, characterized by multiple tumors in endocrine tissues such as the pituitary gland, parathyroid gland, and pancreatic islets [1]. Linkage studies and positional cloning identified the causative gene, MEN1, for this disorder. Over 1,300 mutations, typically truncating, have been identified in MEN1 [2, 3]. The importance of MEN1 inactivation in tumorigenesis is highlighted by the frequency of MEN1 mutations in sporadic endocrine tumors—44% in pancreatic neuroendocrine tumors and 35% in parathyroid adenomas [4, 5]. Heterozygous and conditional Men knockout mice develop tumors in multiple neuroendocrine tissues, Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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