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Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and Men1 null mouse embryonic fibroblast (MEF) cell lines. We demonstrated that the inactivation of menin (the protein product of MEN1) results in increased activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/β-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64412 | GEO | 2015/12/22

SECONDARY ACCESSION(S): PRJNA270977

REPOSITORIES: GEO

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Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

Project description:Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and mouse Men1 null mouse embryonic fibroblast (MEF) cell lines. Tissues from KO mice were used to confirm and assess the findings from the MEN1 clinical samples and further explore the molecular mechanisms of global epigenetic changes following the inactivation of menin. We demonstrated that the inactivation of menin results in enhanced activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/Î²-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development. Global DNA methylation in tissues from patients with MEN1-parathyroid tumors. Thirty-eight human parathyroid specimens were used: 13 sporadic (non-MEN1) parathyroid adenomas, 12 MEN1-parathyroid tumors, 4 parathyroid carcinomas, and 9 normal parathyroids.

2015-12-22 | E-GEOD-64412 | biostudies-arrayexpress

NHGRI Menin ChIP-Chip

Project description:Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. Keywords: ChIP/chip NHGRI Menin ChIP-Chip

2006-07-24 | E-GEOD-5357 | biostudies-arrayexpress

NHGRI Menin ChIP-Chip

2006-07-25 | GSE5357 | GEO

Differential pancreatic islet global gene expression in young heterozygous Men1 mice and wildtype littermates

Project description:Multiple Endocrine Neoplasia Tumor Syndrome type 1 (MEN 1) is an autosomal dominant tumor syndrome affecting individuals with a heterozygous germline mutaion of the MEN1 gene. MEN 1 carriers commonly develop parathyroid, anterior pituitary, duodenal and pancreatic endocrine tumors. The phenotype of existing mouse models for the MEN 1 syndrome, with a germline heterozygous (hz) Men1 gene inactivation, show close resemblance to the human MEN 1 syndrome. Menin, the protein encoded for by the MEN1/Men1 gene, lacks homology with known proteins, and evidence of its involvement in different cellular processes is steadily growing. Several interaction partners have been identified, involving different interaction sites on the menin protein. Accumulating evidence suggests a role for menin in transcriptional regulation, cell cycle control, apoptosis, chromatin modification and DNA damage response and repair. Loss of heterozygosity (LOH) of the MEN1 gene precedes tumor formation in the MEN 1 heterozygous pancreas. We set out to determine if there is a change in gene expression early on in the hz islet, as compared with islets in wildtype (wt) littermates, long before the LOH events occur. We performed a global mRNA expression microarray on islets from young, five-week-old, hz Men1 mice and their wt littermates, and we have subsequently corroborated a subset of the findings on the qPCR and protein level. Islets were isolated and RNA prepared from five five-week-old female mice heterozygous for the Men1 gene and five female wildtype littermates, and then a global gene expression microarray was performed.

2011-06-02 | E-GEOD-29674 | biostudies-arrayexpress

Differential pancreatic islet global gene expression in young heterozygous Men1 mice and wildtype littermates

2011-06-02 | GSE29674 | GEO

A cDNA microarray analysis was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1

Project description:Menin, the product of the MEN1 gene in humans (Men1 in mice), is responsible for the inherited tumor syndrome, multiple endocrine neoplasia type 1 (MEN1). menin interacts with the trithorax group (trxG) proteins (Drosophila) and the mixed-lineage leukemia (MLL) (humans) histone methyltransferase (HMTase) complex, and it alters histone tail modifications and the transcription of target genes. To explore a potential functional implication of menin in HCC, we stably transfected HepG2 or L-02 cells with either vectors or constructs expressing MEN1. A cDNA microarray analysis was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1. To obtain a broader understanding of the molecular network of menin in HCC, the whole genome microarray expression profiling was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1. Comparison of gene expression results from HepG2 or L-02 cells with either vectors or constructs expressing MEN1.

2015-07-07 | E-GEOD-70556 | biostudies-arrayexpress

A cDNA microarray analysis was performed on HepG2 or L-02 cells with either vectors or constructs expressing MEN1

2015-07-07 | GSE70556 | GEO

Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

Project description:Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.

2022-10-14 | PXD031928 | Pride

Expression data of siRNA interfere men1 expression in N2a cell line

Project description:Menin (MEN1) is a critical modulator of tissue development and maintenance.Although menin is abundantly expressed in the nervous system, little is known with regards to its function in the adult brain. To explore molecular mechanisms associated with the phenotypes observed upon neuronal Men1 deletion, we profiled transcriptomes from the Neuro2a(N2a) cells transfected Men1 siRNA USING NimbleGen Mouse gene expression array [100718_MM9_EXP].

2018-07-17 | GSE115344 | GEO

Expression data from Men1 knockout MEFs

Project description:Multiple endocrine neoplasia type1 (MEN1), an inherited autosomal dominant syndrome characterized by the development of endocrine tumors including NETs, results from mutation in the MEN1 gene that encodes the protein menin. In mouse models, heterozygous loss of Men1 leads to multiple endocrine tumors with loss of heterozygocity at the Men1 locus. Men1 interacts with several partners to regulate cellular processes and gene expression through regulating histone modification. We used microarrays to detail the global gene expression change in Men1 knockout MEFs and identified up-regulated genes during this process.

2017-08-22 | GSE87733 | GEO

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