Identifying gene expression changes in fibroblasts treated with an inhibitor targeting MLL1-MENIN complex and depleted for MEN1 gene during reprogramming using RNA-seqeuncing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1001889 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25506300_1.fastq.gz | Fastqsanger.gz | |||
| SRR25506300_2.fastq.gz | Fastqsanger.gz | |||
| SRR25506301_1.fastq.gz | Fastqsanger.gz | |||
| SRR25506301_2.fastq.gz | Fastqsanger.gz | |||
| SRR25506302_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 48 |
Similar Datasets
Project description:Here we investigated the effects of MLL1-MENIN inhibition and MENIN depletion on somatic cell reprogramming.
2024-03-01 | GSE239991 | GEO
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
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.
2012-05-31 | E-GEOD-37775 | biostudies-arrayexpress
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
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
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
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 | GSE196035 | GEO
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
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.
2012-06-01 | GSE37775 | GEO
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.
2012-06-01 | GSE37774 | GEO