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Menin is a Targetable Epigenetic Regulator in Glioblastoma (RNA-Seq)

ABSTRACT: Glioblastomas (GBM) are highly lethal tumors that are refractory to treatment. Here we describe a novel approach to target the epigenetic landscape of GBM and destabilize the glioma progenitor program, leading to inhibition of tumor growth. This is achieved through disruption of the activities of menin, an orphan protein that we demonstrate to play a pro-oncogenic role in GBM. Using pharmacologic and genetic tools, we identify HMGN1, a nucleosome binding chromatin architectural protein as a novel partner for menin. Disruption of this interaction via a newly designed small molecule mimics the major effects of knocking out MEN1, particularly leading to the suppression of H3K27 acetylation marks at genes critical for glioma progenitor identity, as well as promising therapeutic in vivo activity. This work demonstrates a novel role for menin as an epigenetic co-regulator of maintenance and proliferation of glioma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264270 | GEO | 2025/04/17

REPOSITORIES: GEO

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Similar Datasets

Menin is a Targetable Epigenetic Regulator in Glioblastoma (ChIP-Seq)

Project description:Glioblastomas (GBM) are highly lethal tumors that are refractory to treatment. Here we describe a novel approach to target the epigenetic landscape of GBM and destabilize the glioma progenitor program, leading to inhibition of tumor growth. This is achieved through disruption of the activities of menin, an orphan protein that we demonstrate to play a pro-oncogenic role in GBM. Using pharmacologic and genetic tools, we identify HMGN1, a nucleosome binding chromatin architectural protein as a novel partner for menin. Disruption of this interaction via a newly designed small molecule mimics the major effects of knocking out MEN1, particularly leading to the suppression of H3K27 acetylation marks at genes critical for glioma progenitor identity, as well as promising therapeutic in vivo activity. This work demonstrates a novel role for menin as an epigenetic co-regulator of maintenance and proliferation of glioma.

2025-04-17 | GSE264271 | GEO

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

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

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)

2012-05-31 | E-GEOD-37775 | 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

Project description:This SuperSeries is composed of the following subset Series: GSE37774: 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) GSE37775: Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors (mRNA) Refer to individual Series

2012-05-31 | E-GEOD-37776 | biostudies-arrayexpress

Acquired MEN1 mutations mediate resistance to Menin inhibition [CHIP-seq]

Project description:Acute leukemias driven by rearrangements of the Mixed Lineage Leukemia gene (MLLr) or mutants of Nucleophosmin (NPM1c) require the chromatin adapter protein Menin, encoded by the MEN1 gene, to sustain aberrant gene expression programs and maintain stem-like properties. In a phase I first-in-human clinical trial, the Menin-inhibitor SNDX-5613, designed to disrupt the Menin-MLL1 interaction, induced promising clinical responses in leukemia patients6. However, acquired drug resistance was observed in some cases. Here we characterized MEN1 variants that arise on therapy and mediate resistance to Menin inhibition in patients, xenograft models, and a base-editor screen. We show that resistance was associated with emergence of novel MEN1 mutations. These mutants blunted response by impairing drug-target binding, thereby preventing the eviction of Menin-MLL1 complexes from chromatin. Structural modeling revealed a unique interaction mode of the affected residues with the drug, providing the basis for structure-guided development of second-generation compounds. These studies are the first to demonstrate that a small molecule targeting a chromatin-binding protein exerts sufficient selection pressure to drive evolution of a narrow spectrum of escape mutants leading to sustained chromatin occupancy as a novel mechanism of drug resistance in cancer.

2022-12-01 | GSE196036 | GEO

Acquired MEN1 mutations mediate resistance to Menin inhibition [RNA-seq]

2022-12-01 | GSE196035 | GEO

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

Menin deficiency induces autism-like behaviors by regulating Foxg1 transcription and participates in Foxg1-related encephalopathy

Project description:FOXG1 syndrome is a developmental encephalopathy with a high phenotypic variability, which results from FOXG1 mutations. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. Here we report that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome) result in autism-like behaviors, including social defects, increased repetitive behaviors and cognition impairments. We employed multifaceted transcriptome analyses and found that Foxg1 signaling is mostly altered in Men1 deficiency mice, through its regulation over Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 modification. Notably, the described changes in menin deficient mice were rescued by over-expression of Foxg1, leading to normalized spine growth and hippocampal synaptic plasticity. Collectively, these results indicate a putative role of menin in maintaining Foxg1 expression, and menin signaling may serve as Foxg1-related encephalopathy therapeutic targets.

2024-07-03 | GSE261274 | GEO

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