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Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors (mRNA)

ABSTRACT: Inactivating mutations in the MEN1 gene predisposing to the multiple endocrine neoplasia type 1 (MEN1) syndrome can also cause sporadic pancreatic endocrine tumors. MEN1 encodes menin, a subunit of MLL1/MLL2-containing histone methyltransferase complexes that trimethylate histone H3 at lysine 4 (H3K4me3). The importance of menin-dependent H3K4me3 in normal and transformed pancreatic endocrine cells is unclear. To study the role of menin-dependent H3K4me3, we performed in vitro differentiation of wild-type as well as menin-null mouse embryonic stem cells (mESCs) into pancreatic islet-like endocrine cells (PILECs). Gene expression analysis and genome-wide H3K4me3 ChIP-Seq profiling in wild-type and menin-null mESCs and PILECs revealed menin-dependent H3K4me3 at the imprinted Dlk1-Meg3 locus in mESCs, and all four Hox loci in differentiated PILECs. Specific and significant loss of H3K4me3 and gene expression was observed for genes within the imprinted Dlk1-Meg3 locus in menin-null mESCs and the Hox loci in menin-null PILECs. Given that the reduced expression of genes within the DLK1-MEG3 locus and the HOX loci is associated with MEN1-like sporadic tumors, our data suggests a possible role for menin-dependent H3K4me3 at these genes in the initiation and progression of sporadic pancreatic endocrine tumors. Furthermore, our investigation also demonstrates that menin-null mESCs can be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null mESC-derived specialized cell types for genome-wide high-throughput studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE37775 | GEO | 2012/06/01

SECONDARY ACCESSION(S): PRJNA163663

REPOSITORIES: GEO

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Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors (ChIP-Seq)

Project description:Inactivating mutations in the MEN1 gene predisposing to the multiple endocrine neoplasia type 1 (MEN1) syndrome can also cause sporadic pancreatic endocrine tumors. MEN1 encodes menin, a subunit of MLL1/MLL2-containing histone methyltransferase complexes that trimethylate histone H3 at lysine 4 (H3K4me3). The importance of menin-dependent H3K4me3 in normal and transformed pancreatic endocrine cells is unclear. To study the role of menin-dependent H3K4me3, we performed in vitro differentiation of wild-type as well as menin-null mouse embryonic stem cells (mESCs) into pancreatic islet-like endocrine cells (PILECs). Gene expression analysis and genome-wide H3K4me3 ChIP-Seq profiling in wild-type and menin-null mESCs and PILECs revealed menin-dependent H3K4me3 at the imprinted Dlk1-Meg3 locus in mESCs, and all four Hox loci in differentiated PILECs. Specific and significant loss of H3K4me3 and gene expression was observed for genes within the imprinted Dlk1-Meg3 locus in menin-null mESCs and the Hox loci in menin-null PILECs. Given that the reduced expression of genes within the DLK1-MEG3 locus and the HOX loci is associated with MEN1-like sporadic tumors, our data suggests a possible role for menin-dependent H3K4me3 at these genes in the initiation and progression of sporadic pancreatic endocrine tumors. Furthermore, our investigation also demonstrates that menin-null mESCs can be differentiated in vitro into islet-like endocrine cells, underscoring the utility of menin-null mESC-derived specialized cell types for genome-wide high-throughput studies. Genome-wide mapping of H3K4me3 and microarray gene expression profiling in TC-1 wild-type (WT) mESCs, menin-null (Men1-ko) mESCs (3.2N), pancreatic islet-like endocrine cells (PILECs) derived from WT mESCs, and PILECs derived from Men1-ko mESCs.

2012-06-01 | E-GEOD-37774 | biostudies-arrayexpress

Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors (mRNA)

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Project description:MEN1 is a tumor suppressor gene loss of which causes lipoma (fatty tumors under the skin) and many other endocrine and non-endocrine tumors. It's target genes in fat cells (adipocytes) are unknown. Gene expression in adipocytes that were in vitro differentiated from mouse embryonic stem cells (mESCs) of Men1-nul l(Men1-KO) and WT mice were compared to assess the expression of genes upon menin loss in adipocytes that could lead to the deveopment of lipoma. mESCs (Men1-null and WT) were in vitro differentaited into adipocytes. Positive oil red O staining indicated successful differentiation into adipocytes. The cells were processed for RNA isolation. RNA preps were used for microarray analysis.

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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.

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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.

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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

Expression changes in mouse embryo fibroblasts associated with the loss of menin (menin-null)

Project description:Multiple endocrine neoplasia, type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized primarily by endocrine tumors of the parathyroids, anterior pituitary and enteropancreatic endocrine tissues. Affected individuals carry a germline loss-of-function mutation of the MEN1 gene, and tumors arise after loss of the second allele. Homozygous loss of Men1 in the germline of mice results in early embryonic lethality, with defective development of neural tube, heart, liver, and craniofacial structures. We generated immortalized Wild type (Wt) and menin-null mouse embryo fibroblast (MEF) cell lines and evaluated their characteristics, including global expression patterns. The Wt and menin-null cell lines were aneuploid, and the nulls did not display tumorigenic characteristics in soft-agar assay. Expression arrays in menin-null MEFs revealed altered expression of several extracellular matrix proteins that are critical in organogenesis. Specifically, transcripts for fibulin-2 (Fbln2), periostin (Postn) and versican (Cspg2, chondroitin sulfate proteoglycan), genes critical for the developing heart and known to be induced by TGF-beta, were decreased in their expression in menin-null MEFs. Fbln2 expression was the most affected, and the reduction in menin-null MEFs for Fbln2, Postn and Cspg2 was 16.18, 5.37 and 2.15-fold respectively. Menin-null MEFs also showed poor response to TGF-beta-induced Smad3-mediated transcription in a reporter assay, supporting a role for menin in this pathway. The expression changes associated with the loss of the tumor suppressor menin provide insights into the defective organogenesis observed during early embryonic development in Men1-null mouse embryos. Keywords: Wild type and menin-null mouse embryo fibroblasts

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