Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c
- Satyajit K. Karnik*,
- Christina M. Hughes†,
- Xueying Gu*,
- Orit Rozenblatt-Rosen†,
- Graeme W. McLean*,
- Yue Xiong‡,
- Matthew Meyerson†, and
- Seung K. Kim*,§,¶
- Departments of *Developmental Biology and §Medicine (Oncology Division), Stanford University School of Medicine, Stanford, CA 94305-5329; †Department of Medical Oncology, Dana–Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA 02115; and ‡Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Program in Molecular Biology and Biotechnology, University of North Carolina, Chapel Hill, NC 27599
-
Edited by Arnold J. Levine, Institute for Advanced Study, Princeton, NJ (received for review April 28, 2005)
Abstract
Menin, the product of the Men1 gene mutated in familial multiple endocrine neoplasia type 1 (MEN1), regulates transcription in differentiated cells. Menin associates with and modulates the histone methyltransferase activity of a nuclear protein complex to activate gene expression. However, menin-dependent histone methyltransferase activity in endocrine cells has not been demonstrated, and the mechanism of endocrine tumor suppression by menin remains unclear. Here, we show that menin-dependent histone methylation maintains the in vivo expression of cyclin-dependent kinase (CDK) inhibitors to prevent pancreatic islet tumors. In vivo expression of CDK inhibitors, including p27 and p18, and other cell cycle regulators is disrupted in mouse islet tumors lacking menin. Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters. Moreover, H3 Lys-4 methylation associated with p27 and p18 is reduced in islet tumors from Men1 mutant mice. Thus, H3 Lys-4 methylation is a crucial function of menin in islet tumor suppression. These studies suggest an epigenetic mechanism of tumor suppression: by promoting histone modifications, menin maintains transcription at multiple loci encoding cell cycle regulators essential for endocrine growth control.
Footnotes
-
↵ ¶ To whom correspondence should be addressed. E-mail: seungkim{at}cmgm.stanford.edu.
-
This paper was submitted directly (Track II) to the PNAS office.
-
Abbreviations: MEN, multiple endocrine neoplasia; TrxG, trithorax group; Lys-4, lysine 4; HMTase, histone methyltransferase; CDK, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; siRNA, small interfering RNA; PP, primer pair.
- Copyright © 2005, The National Academy of Sciences
