ATAC-seq of Chd7 WT and mutant cerebellar granule neuron progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76984 | GEO | 2017/01/20
SECONDARY ACCESSION(S): PRJNA309175
REPOSITORIES: GEO
Similar Datasets
Project description:We identified genes that are regulated by Chd7 in GNPs
2017-01-20 | GSE72207 | GEO
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: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.
2017-01-20 | GSE76975 | GEO
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.
2017-11-22 | GSE107252 | GEO
Project description:We mapped the binding sites of Chd7 in cerebellar granule cells, and compared with the pattern of H3K27ac. To examine the impact of Chd7 loss to Top2b binding, we mapped the binding sites of Top2b in control and Chd7 mutant cells
2017-01-20 | GSE93719 | GEO
Project description:Snf2l and the closely related protein, Snf2h, play a critical role in embryonic and post-natal brain development. Murine models lacking functional Snf2h or Snf2l point to complementary activities of these remodelers; Snf2h cKO mice present with a significantly reduced cerebellum, while Snf2l Ex6DEL cerebella are larger than their wild-type counterparts. Granule neuron progenitors (GNPs) isolated from Ex6DEL cerebella display delayed cell cycle exit and hindered terminal differentiation compared to wild-type littermates. Moreover, loss of Snf2l activity results in widespread transcriptome shifts which underlie the Ex6DEL GNP differentiation phenotype. In particular, key transcription factors (TFs) are differentially expressed without Snf2l remodelling activity. We confirm that ERK pathway activation is misregulated in Ex6DEL GNPs, possibly in response to elevated fibroblast growth factor 8 (Fgf8) expression in these cultures. We find that Snf2l activity maintains the chromatin landscape throughout GNP differentiation, as Ex6DEL cultures have a global increase in chromatin accessibility. We suggest that Snf2l-mediated chromatin condensation is responsible for proper regulation of gene expression programs in GNP differentiation.
2019-12-31 | GSE122173 | GEO
Project description:Snf2l and the closely related protein, Snf2h, play a critical role in embryonic and post-natal brain development. Murine models lacking functional Snf2h or Snf2l point to complementary activities of these remodelers; Snf2h cKO mice present with a significantly reduced cerebellum, while Snf2l Ex6DEL cerebella are larger than their wild-type counterparts. Granule neuron progenitors (GNPs) isolated from Ex6DEL cerebella display delayed cell cycle exit and hindered terminal differentiation compared to wild-type littermates. Moreover, loss of Snf2l activity results in widespread transcriptome shifts which underlie the Ex6DEL GNP differentiation phenotype. In particular, key transcription factors (TFs) are differentially expressed without Snf2l remodelling activity. We confirm that ERK pathway activation is misregulated in Ex6DEL GNPs, possibly in response to elevated fibroblast growth factor 8 (Fgf8) expression in these cultures. We find that Snf2l activity maintains the chromatin landscape throughout GNP differentiation, as Ex6DEL cultures have a global increase in chromatin accessibility. We suggest that Snf2l-mediated chromatin condensation is responsible for proper regulation of gene expression programs in GNP differentiation.
2019-12-31 | GSE122172 | 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: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.
2021-04-07 | GSE164360 | GEO
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