title: Dynamic epigenetic regulation by menin during pancreatic islet tumor formation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts. High Magnetic Field Laboratory, Chinese Academy of Sciences, 350 Shushanhu RD, Hefei, Anhui Province, 230031, P. R. China.
authors.forename: Wenchu
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Nathan
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Aruna
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Agoston
authors.initials: A
authors.lastname: Agoston
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Cancer program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts. matthew_meyerson@dfci.harvard.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D007516:Adenoma, Islet Cell; D000818:Animals; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D006657:Histones; C559768:IGF2BP2 protein, mouse; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins