RNA-seq of Chd7 wild type and mutant granule neuron progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE72207 | GEO | 2017/01/20
SECONDARY ACCESSION(S): PRJNA293356
REPOSITORIES: GEO
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Project description:We performed array-based expression profiling to determine genes regulated by Chd7 and Top2b in CGNs. Our data show Chd7 and Top2b coregulate a common set of neuronal genes. Furthermore, we compared the gene expession in proliferating and postmitotic granule cells.
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Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to stimulate proliferation of granule neuron precursor cells (GNPs) in the cerebellum. Deregulation of Shh target genes often results in unrestrained GNP proliferation and eventually medulloblastoma (MB), the most common pediatric brain malignancy. Gene expression profiling was coupled with transcription factor binding location analysis to determine the Gli1-controlled transcriptional regulatory networks in GNPs and medulloblastoma cells. We detected significant overlap, as well as differences, in the Gli1-controlled transcriptional regulatory networks in GNPs and MBs. We determined the presence of gene expression in each dataset. There were 9260 genes expressed in Gli1-FLAG GNPs and 9185 genes expressed in Gli1-FLAG;Ptc+/- tumors; 8691 of which are in common. The large overlap is consistent with the cellular origin of these tumors. When the genes detectably expressed were intersected with our binding data, there were only 132 putative Gli1 target genes shared by both cell populations. Due to the heightened activation of the Hh pathway in tumors relative to GNPs, we further deduced direct Gli1 target genes exclusive to tumors by determining significantly induced genes in tumors versus in Ptc+/- GNPs. We identified at least 116 tumor-specific Gli1 target genes. These data suggest that tumor formation is accompanied by a tremendous change in the battery of Gli target genes. Presence of gene expression was determined for all samples: Gli1-FLAG-expressing GNPs, Ptc+/- GNPs, and Gli1-FLAG;Ptc+/-medulloblastomas. These datasets were intersected with chIP-chip data to determine potential direct Gli1 target genes. Differential gene expression was determined by comparing expression profiles from medulloblastoma tumors to those from Ptc+/- GNPs.
2010-06-16 | E-GEOD-17702 | biostudies-arrayexpress
Project description:Regulation of chromatin plays fundamental roles in the normal development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that prominently affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes the accessibility and activity of enhancers in granule cell precursors. Remarkably, in vivo profiling of genome architecture reveals that CHD7 operates locally to stimulate enhancer activation, thereby driving the expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated prominently with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define CHD7 function in the regulation of the epigenome in granule cell precursors and identify a surprising link of CHD7 to the control of cerebellar cortical morphogenesis, with potential implications for our understanding of CHARGE syndrome.
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Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to stimulate proliferation of granule neuron precursor cells (GNPs) in the cerebellum. Deregulation of Shh target genes often results in unrestrained GNP proliferation and eventually medulloblastoma, the most common pediatric brain malignancy. Transcription factor binding location analysis (chIP-chip) revealed 510 and 1,060 genomic loci bound by Gli1 with high confidence in murine GNP and medulloblastoma cells, respectively. In primary tumors, Gli1 associated with only one-third of the Gli1-bound regions in GNPs. Gene expression profiling, coupled with our binding results, indicated that there were more than one hundred target genes in common between the two cell populations, and importantly, there was an equivalent number of tumor-specific targets. These results indicate that the transformation of normal GNPs into deadly tumor cells is accompanied by some changes in the battery of genes regulated by Gli1.
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Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to stimulate proliferation of granule neuron precursor cells (GNPs) in the cerebellum. Deregulation of Shh target genes often results in unrestrained GNP proliferation and eventually medulloblastoma (MB), the most common pediatric brain malignancy. Gene expression profiling was coupled with transcription factor binding location analysis to determine the Gli1-controlled transcriptional regulatory networks in GNPs and medulloblastoma cells. We detected significant overlap, as well as differences, in the Gli1-controlled transcriptional regulatory networks in GNPs and MBs. We determined the presence of gene expression in each dataset. There were 9260 genes expressed in Gli1-FLAG GNPs and 9185 genes expressed in Gli1-FLAG;Ptc+/- tumors; 8691 of which are in common. The large overlap is consistent with the cellular origin of these tumors. When the genes detectably expressed were intersected with our binding data, there were only 132 putative Gli1 target genes shared by both cell populations. Due to the heightened activation of the Hh pathway in tumors relative to GNPs, we further deduced direct Gli1 target genes exclusive to tumors by determining significantly induced genes in tumors versus in Ptc+/- GNPs. We identified at least 116 tumor-specific Gli1 target genes. These data suggest that tumor formation is accompanied by a tremendous change in the battery of Gli target genes.
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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.
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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: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.
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Project description:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine granule neuron precursors, chronically induced at embryonic stages of development.
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