Convergence of BMI1 and CHD7 on ERK signalling in medulloblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE83696 | GEO | 2019/06/23
REPOSITORIES: GEO
Similar Datasets
Project description:Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. Here we identify a synergic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors and we elucidate the molecular mechanisms underpinning the CHD7-BMI1-MAPK regulatory axis which mediates the anti-tumor effect of these inhibitors in vitro and in vivo, in a pre-clinical mouse model. Enhanced ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy.
2022-02-28 | GSE172363 | GEO
Project description:We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1High;CHD7Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression. These findings extend current knowledge of the role of BMI1 and CHD7 in medulloblastoma pathogenesis, and they raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of MB with low expression levels of CHD7.
| S-EPMC5732319 | biostudies-literature
Project description:Identification of BMI1, RYBP and H2AK119UB interactome in Glioblastoma (GBM) to elucidate BMI1 roles independent of the PRC1-complex in GBM.
2021-09-09 | PXD022057 | Pride
Project description:CHD7 is a member of the chromodomain helicase DNA binding domain family of ATP-dependent chromatin remodeling enzymes. De novo mutation of the CHD7 gene is a major cause of CHARGE syndrome, a genetic disease characterized by a complex constellation of birth defects. To gain insight to the function of CHD7, we mapped the distribution of the CHD7 protein on chromatin using the approach of chromatin immunoprecipitation on tiled microarrays (ChIP-chip). These studies were performed in human colorectal carcinoma cells, human neuroblastoma cells, and mouse embryonic stem (ES) cells before and after differentiation into neural precursor cells. The results indicate that CHD7 localizes to discrete locations along chromatin that are specific to each cell type, and that the cell-specific binding of CHD7 correlates with a subset of histone H3 methylated at lysine 4 (H3K4me). The CHD7 sites change concomitantly with H3K4me patterns during ES cell differentiation, suggesting that H3K4me is part of the epigenetic signature that defines lineage-specific association of CHD7 with specific sites on chromatin. Furthermore, the CHD7 sites are predominantly located distal to transcription start sites, most often contained within DNase hypersensitive sites, frequently conserved, and near genes expressed at relatively high levels. These features are similar to those of gene enhancer elements, raising the possibility that CHD7 functions in enhancer mediated transcription, and that the congenital anomalies in CHARGE syndrome are due to alterations in transcription of tissue-specific genes normally regulated by CHD7 during development. ChIP-chip experiments were performed for CHD7 and H3K4 mono-,di-, and trimethylation modifications in 4 cells types: human DLD1 and SH-SY5Y; mouse ES and differentiated neural precursor cells derived from mouse ES cells. Microarrays used in these experiments tiled all or subset of ENCODE regions (in mouse, analogous ENCODE regions were assayed). At least two biological replicates were performed for each CHD7 ChIP experiment; H3K4 ChIP's were performed once in each cell type.
2009-01-22 | E-GEOD-14460 | biostudies-arrayexpress
Project description:Mutation of the gene encoding the ATP-dependent chromatin remodeler CHD7 causes CHARGE syndrome. The mechanisms underlying the neurodevelopmental deficits associated with the syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems and autistic features, are not known. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we show that deletion of Chd7 from cerebellar granule cell precursors (GCps) in the mouse results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay and motor deficits. Genome-wide expression profiling revealed downregulated Reln gene expression in Chd7-deficient GCps. Recessive RELN mutations is associated with severe cerebellar hypoplasia in humans. We provide molecular and genetic evidence that reduced Reln expression contributes substantially to the GCp proliferative defect and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we show that CHD7 is necessary for the maintenance of an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln and provides the first evidence that a mammalian CHD protein controls brain development by modulating chromatin accessibility in neuronal progenitors in vivo.
2017-01-01 | GSE90466 | GEO
Project description:Gene expression changes were measured between mouse ES cells of three genotypes: WT Chd7, Heterzygous Chd7 Null, Homozygous Chd7 Null. The hypothesis being tested was that CHD7, a chromatin remodeling protein, functions as a transcriptional regulator. This experiment was performed to detect gene targets of CHD7-mediated regulation. We report the genome-wide binding profile of CHD7, the protein implicated in CHARGE syndrome, in mouse ES cells using ChIP-Seq technology. Combining these data with other genomic datasets, we discover CHD7 to colocalize with other transcription factors including Oct4, Nanog, Sox2, and p300 at gene enhancer elements to regulate ES cell specific gene expression. Chd7 wildtype, heterozygous, and homozygous ES cells derived from preimplantation embryos were grown on feeder cells and total RNA was isolated using Trizol. The ratio of ES to feeder cells was estimated at 5:1. ChIP sequencing of CHD7 and p300 in mouse ES cells
2010-06-15 | E-GEOD-22341 | biostudies-arrayexpress
Project description:BMI1-silenced Prostate cancer cells exhibited a significant change in the expression of several proliferation-associated genes. These included Cyclin-D1, BCL2, IL and NF-kappaB. An increased expression of p16, p15 and TIMP3 in BMI1-silenced tumor cells was observed List of Selected Genes Modulated by BMI1-supression in Prostate cancer Cells
2013-02-05 | GSE44049 | GEO
Project description:The epigenetic repressor BMI1 plays an integral role in promoting the self-renewal and proliferation of many adult stem cell populations, and also tumor types, primarily through silencing the Cdkn2a locus, which encodes the tumor suppressors p16Ink4a and p19Arf. However, in cutaneous melanoma, BMI1 drives epithelial-mesenchymal transition programs, and thus metastasis, while having little impact on proliferation or primary tumor growth. This raised questions about the requirement and role for BMI1 in melanocyte stem cell (MeSC) biology. Here, we demonstrate that murine melanocyte-specific Bmi1 deletion causes premature hair greying, which results from gradual MeSC loss. We establish that MeSC loss begins in the second hair cycle and is accompanied by melanocyte depletion. RNA-seq of MeSCs revealed that Bmi1 deletion induces transcriptional upregulation of p16Ink4a and p19Arf, mirroring the central role of BMI1 in other stem cell contexts. Additionally, the glutathione S-transferase enzymes Gsta1 and Gsta2 are downregulated by BMI1 loss, raising the possibility that MeSCs could be susceptible to oxidative stress. Accordingly, treatment with the antioxidant N-acetyl cysteine (NAC) partially rescued melanocyte expansion. Together, our data establish a critical role for BMI1 in MeSC maintenance that reflect a partial role for suppression of oxidative stress, and likely transcriptional repression of Cdkn2a.
2024-01-28 | GSE194373 | GEO
Project description:Mutations in the chromatin remodeller CHD7 cause CHARGE syndrome (CS). Importantly, children with CS exhibit moderate to severe neurological and behaviour symptoms including autism. However, the neural substrates underlying these symptoms remain largely unknown. Here we show that zebrafish chd7 mutant display a nighttime hyperactivity behavioural phenotype and exhibit altered number and positioning of GABAergic neurons in brain regions. Using a transcriptomic approach, we identified many genes involved in cell adhesion, migration and receptor signalling that are dysregulated in the chd7 brain. We also show an abnomal hyperactivation of ERK signalling contributing to the GABAergic defects. A phenotype-based screen of 3850 compounds identifies a lead compound, ephedrine that ameliorates GABAergic and behavioural anomalies in chd7 animals. Our study identifies CHD7 as critical regulator of GABAergic network development. Importantly, we provide novel insight into the mechanisms underlying the neurological deficits in CS and identify a new therapeutic for CS-associated neurobehavioural symptoms.
2019-10-31 | GSE139623 | GEO
Project description:BMI1-silenced Prostate cancer cells exhibited a significant change in the expression of several proliferation-associated genes. These included Cyclin-D1, BCL2, IL and NF-kappaB. An increased expression of p16, p15 and TIMP3 in BMI1-silenced tumor cells was observed List of Selected Genes Modulated by BMI1-supression in Prostate cancer Cells qPCR gene expression profiling. LNCaP and BMI1-silenced LNCaP cells were used as indicated in the summary. Equal amount of total RNA from each group was pooled prior to gene expression analysis.
2013-02-05 | E-GEOD-44049 | biostudies-arrayexpress