Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation

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Abstract

We reported that inactivation of menin (the protein product of MEN1 ) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased β-cell proliferation. In vivo, our results showed that the levels of serum insulin were increased in the RIP-TVA mice with RCASBP- Dnmt1 infection compared with wild-type control mice with RCASBP- Dnmt1 infection. Furthermore, we confirmed that mRNA and protein expression of Dnmt1 as well as Dnmt1 enzyme activity were upregulated in the RIP-TVA mice with RCASBP- Dnmt1 infection compared with wild-type control mice with RCASBP- Dnmt1 infection. Finally, we demonstrated that upregulation of Dnmt1 resulted in hyperplasia through β-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet β-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors.

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The DNA methyltransferases of mammals.

T Bestor (2000)

The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.

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Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.

Rajesh Thakker, Manuel C. Lemos (2007)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610-amino acid protein referred to as menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter), and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. (c) 2007 Wiley-Liss, Inc.

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Regulation of mammalian DNA methyltransferases: a route to new mechanisms.

Hélène Denis, Matladi Ndlovu, François Fuks (2011)

DNA methyltransferases (DNMTs) establish and maintain DNA methylation patterns at specific regions of the genome, thereby contributing to gene regulation. It is becoming evident that an intricate web of pathways target DNMTs to these genomic regions. Here, we review the understanding of these regulatory mechanisms and provide an overview of the new findings, emphasizing the emerging scenario in which several levels of regulation are coordinated to control DNMTs. The mechanisms involved include the dynamic interplay between interdependent post-translational modifications that regulate DNMTs, post-transcriptional regulation by miRNAs and the emerging role of non-coding RNA in targeting mammalian DNMTs. The analysis of these mechanisms is imperative to the understanding of the role of DNA methylation in regulating gene expression during development and in disease.