Dynamic epigenetic regulation by menin during pancreatic islet tumor formation

Mol Cancer Res. 2015 Apr;13(4):689-98. doi: 10.1158/1541-7786.MCR-14-0457. Epub 2014 Dec 23.


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.

MeSH terms

  • Adenoma, Islet Cell
  • Animals
  • Epigenesis, Genetic*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Histones / metabolism
  • Humans
  • Methylation
  • Mice
  • Molecular Sequence Data
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology*
  • Proto-Oncogene Proteins / genetics*
  • RNA-Binding Proteins / genetics*


  • Histones
  • IGF2BP2 protein, mouse
  • Men1 protein, mouse
  • Proto-Oncogene Proteins
  • RNA-Binding Proteins