Chromatin landscape of medulloblastoma reveals context dependent driver
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ABSTRACT:
PROVIDER: EGAS00001006741 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Medulloblastoma, a common malignant pediatric brain tumor that typically originating from the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of epigenomic abnormalities in their progression. To prove this significance, the development and use of animal models that closely recapitulate the disease have been highly effective. However, due to substantial time and cost limitations of developing genetically engineered mouse models, a complete understanding of the oncogenic potential of chromatin modifiers’ mutations found in human medulloblastomas is still elusive. In this study, we address this by CRISPR-mediated gene editing platform to knock out chromatin modifiers mutated human in SHH-subgroup medulloblastoma as well as the Ptch1 gene in cerebellar granule neuron progenitors. We functionally screened molecules involved tumor formation, identifying CHD7 and KMT2C as tumor suppressor genes. Multi-layered omics analysis revealed that these molecules epigenetically regulate the expression of Neurod1 that encodes a transcription factor crucial for neuronal differentiation, through histone H3 modification. Mutations impairing these factors suppress Neurod1, accelerating tumor growth. Conversely, forced expression of Neurod1 inhibits proliferation and promotes differentiation, underscoring its role as a key regulator in medulloblastoma aggressiveness. These findings not only demonstrate converging epigenomic abnormalities in SHH-subgroup medulloblastoma but also hold significant potential for evaluating epigenetic drugs targeting medulloblastoma, advancing the development of novel treatments.
2025-03-30 | GSE263361 | GEO
Project description:Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma.
| S-EPMC11735403 | biostudies-literature
Project description:Medulloblastoma, a common malignant pediatric brain tumor that typically originating from the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of epigenomic abnormalities in their progression. To prove this significance, the development and use of animal models that closely recapitulate the disease have been highly effective. However, due to substantial time and cost limitations of developing genetically engineered mouse models, a complete understanding of the oncogenic potential of chromatin modifiers’ mutations found in human medulloblastomas is still elusive. In this study, we address this by CRISPR-mediated gene editing platform to knock out chromatin modifiers mutated human in SHH-subgroup medulloblastoma as well as the Ptch1 gene in cerebellar granule neuron progenitors. We functionally screened molecules involved tumor formation, identifying CHD7 and KMT2C as tumor suppressor genes. Multi-layered omics analysis revealed that these molecules epigenetically regulate the expression of Neurod1 that encodes a transcription factor crucial for neuronal differentiation, through histone H3 modification. Mutations impairing these factors suppress Neurod1, accelerating tumor growth. Conversely, forced expression of Neurod1 inhibits proliferation and promotes differentiation, underscoring its role as a key regulator in medulloblastoma aggressiveness. These findings not only demonstrate converging epigenomic abnormalities in SHH-subgroup medulloblastoma but also hold significant potential for evaluating epigenetic drugs targeting medulloblastoma, advancing the development of novel treatments.
2025-03-30 | GSE263360 | GEO
Project description:Medulloblastoma, a common malignant pediatric brain tumor that typically originating from the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of epigenomic abnormalities in their progression. To prove this significance, the development and use of animal models that closely recapitulate the disease have been highly effective. However, due to substantial time and cost limitations of developing genetically engineered mouse models, a complete understanding of the oncogenic potential of chromatin modifiers’ mutations found in human medulloblastomas is still elusive. In this study, we address this by CRISPR-mediated gene editing platform to knock out chromatin modifiers mutated human in SHH-subgroup medulloblastoma as well as the Ptch1 gene in cerebellar granule neuron progenitors. We functionally screened molecules involved tumor formation, identifying CHD7 and KMT2C as tumor suppressor genes. Multi-layered omics analysis revealed that these molecules epigenetically regulate the expression of Neurod1 that encodes a transcription factor crucial for neuronal differentiation, through histone H3 modification. Mutations impairing these factors suppress Neurod1, accelerating tumor growth. Conversely, forced expression of Neurod1 inhibits proliferation and promotes differentiation, underscoring its role as a key regulator in medulloblastoma aggressiveness. These findings not only demonstrate converging epigenomic abnormalities in SHH-subgroup medulloblastoma but also hold significant potential for evaluating epigenetic drugs targeting medulloblastoma, advancing the development of novel treatments.
2025-03-30 | GSE263359 | GEO
Project description:Medulloblastoma, a common malignant pediatric brain tumor that typically originating from the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of epigenomic abnormalities in their progression. To prove this significance, the development and use of animal models that closely recapitulate the disease have been highly effective. However, due to substantial time and cost limitations of developing genetically engineered mouse models, a complete understanding of the oncogenic potential of chromatin modifiers’ mutations found in human medulloblastomas is still elusive. In this study, we address this by CRISPR-mediated gene editing platform to knock out chromatin modifiers mutated human in SHH-subgroup medulloblastoma as well as the Ptch1 gene in cerebellar granule neuron progenitors. We functionally screened molecules involved tumor formation, identifying CHD7 and KMT2C as tumor suppressor genes. Multi-layered omics analysis revealed that these molecules epigenetically regulate the expression of Neurod1 that encodes a transcription factor crucial for neuronal differentiation, through histone H3 modification. Mutations impairing these factors suppress Neurod1, accelerating tumor growth. Conversely, forced expression of Neurod1 inhibits proliferation and promotes differentiation, underscoring its role as a key regulator in medulloblastoma aggressiveness. These findings not only demonstrate converging epigenomic abnormalities in SHH-subgroup medulloblastoma but also hold significant potential for evaluating epigenetic drugs targeting medulloblastoma, advancing the development of novel treatments.
2025-03-30 | GSE263358 | GEO
Project description:Medulloblastoma, a common malignant pediatric brain tumor that typically originating from the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of epigenomic abnormalities in their progression. To prove this significance, the development and use of animal models that closely recapitulate the disease have been highly effective. However, due to substantial time and cost limitations of developing genetically engineered mouse models, a complete understanding of the oncogenic potential of chromatin modifiers’ mutations found in human medulloblastomas is still elusive. In this study, we address this by CRISPR-mediated gene editing platform to knock out chromatin modifiers mutated human in SHH-subgroup medulloblastoma as well as the Ptch1 gene in cerebellar granule neuron progenitors. We functionally screened molecules involved tumor formation, identifying CHD7 and KMT2C as tumor suppressor genes. Multi-layered omics analysis revealed that these molecules epigenetically regulate the expression of Neurod1 that encodes a transcription factor crucial for neuronal differentiation, through histone H3 modification. Mutations impairing these factors suppress Neurod1, accelerating tumor growth. Conversely, forced expression of Neurod1 inhibits proliferation and promotes differentiation, underscoring its role as a key regulator in medulloblastoma aggressiveness. These findings not only demonstrate converging epigenomic abnormalities in SHH-subgroup medulloblastoma but also hold significant potential for evaluating epigenetic drugs targeting medulloblastoma, advancing the development of novel treatments.
2025-03-30 | GSE293000 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE33199: A mouse model of the most aggressive subgroup of human medulloblastoma [Mouse430_2] GSE33200: A mouse model of the most aggressive subgroup of human medulloblastoma [HT_MG-430_PM] Refer to individual Series
2012-02-29 | E-GEOD-33201 | biostudies-arrayexpress
Project description:Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. To identify mutations that drive medulloblastoma we sequenced the entire genomes of 37 tumours and matched normal blood. One hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma: several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumours (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development. A total of 76 pediatric medulloblastoma samples were analyzed, representing 4 expression classes
2012-07-05 | E-GEOD-37418 | biostudies-arrayexpress
Project description:DDX3X is an ATP-dependent RNA helicase. Missense mutations in DDX3X gene are known to occur in WNT, SHH subgroup medulloblastomas. The role of DDX3X in medulloblastoma biology was studied by downregulating its expression in a SHH subgroup Daoy medulloblastoma cell line. DDX3X knockdown resulted in considerable reduction in proliferation, clonogenic potential and anchorage-independent growth of the medulloblastoma cells. Transcriptome analysis was performed to delineate the molecular mechanism underlying reduction in the malignant potential of the medulloblastoma cells upon DDX3X knockdown. Exogenous expression of three DDX3X missense mutants in the DDX3X knockdown cells could restore the malignant potential of the medulloblastoma cells.
2023-03-31 | GSE201967 | GEO
Project description:Medulloblastoma could be classified into four subtypes: Wnt, Shh, Group 3, and Group 4. Subtypes of medulloblastoma have distinct epigenetic properties. We report that a chromatin regulator SMARCA4/Brg1 controls a transcriptional program that specifically required for Shh-type medulloblastoma identity and proliferation. We show that Brg1 deletion significantly inhibited tumor formation and progression in a mouse medulloblastoma model. Genomic experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1, and REST to regulate the expression of both oncogenes and tumor suppressors. Shh-type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate expression of medulloblastoma genes. Brg1 is important for the growth of a human medulloblastoma cell line and Brg1-regulated pathways are conserved in human Shh-type medulloblastoma. This study reveals a novel epigenetic mechanism that controls medulloblastoma development and provides a rationale for developing subtype-specific treatment strategies.
2016-09-14 | GSE69672 | GEO