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Dynamic epigenetic regulation by menin during pancreatic islet tumor formation

Wenchu Lin1, Hideo Watanabe2, Shouyong Peng2

  • 1Department 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.

Molecular Cancer Research : MCR
|December 25, 2014
PubMed
Abstract

Insights

Loss of the tumor suppressor gene MEN1 alters epigenetic marks in pancreatic islet cells, impacting gene expression and potentially contributing to pancreatic neuroendocrine tumor (PanNET) development. This affects key genes like IGF2BP2.

Area of Science:

  • Endocrinology and Metabolism
  • Cancer Epigenetics
  • Molecular Oncology

Background:

  • The tumor suppressor gene MEN1 is frequently mutated in pancreatic neuroendocrine tumors (PanNETs) and is linked to the MEN-1 cancer syndrome.
  • Menin, the protein product of MEN1, interacts with histone methyltransferases (HMTs) MLL1 and MLL4, forming menin-HMT complexes.
  • Understanding the role of menin-HMT complexes in epigenetic regulation is crucial for PanNET tumorigenesis.

Purpose of the Study:

  • To elucidate the role of histone H3 lysine 4 trimethylation (H3K4me3) mediated by menin-HMT complexes in PanNET formation.
  • To identify menin-dependent transcripts and target genes in pancreatic islets.
  • To investigate the epigenetic regulation of IGF2BP2 by Men1.

Main Methods:

  • Genome-wide mapping of H3K4me3 signals in pancreatic islets using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq).
  • Integrative analysis of gene expression profiles and H3K4me3 levels.
  • Assessment of histone H3K27me3 levels and the impact of RBP2 (KDM5A) ablation.

Main Results:

  • Loss of Men1 leads to altered H3K4me3 and enriched H3K27me3 at target gene promoters.
  • Menin deficiency dynamically regulates the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2).
  • Ablation of the H3K4 demethylase RBP2 partially reverses decreased IGF2BP2 expression in Men1-deficient islets.

Conclusions:

  • Loss of Men1 in pancreatic islet cells significantly alters the epigenetic landscape of its target genes.
  • Epigenetic profiling in Men1-deficient cells provides insight into molecular events during pancreatic islet tumorigenesis.
  • Menin-dependent histone modifications play a critical role in regulating gene expression relevant to PanNET development.

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