Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenomic Activation of Enhancers in Granule Cell Precursors by CHARGE Syndrome Protein CHD7 Regulates Gyrification of the Mammalian Cerebellum

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE164360 | GEO | 2021/04/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

CHD7 controls cerebellar development via Reelin

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

Epigenomic Activation of Enhancers in Granule Cell Precursors by CHARGE Syndrome Protein CHD7 Regulates Gyrification of the Mammalian Cerebellum

Project description:Epigenomic Activation of Enhancers in Granule Cell Precursors by CHARGE Syndrome Protein CHD7 Regulates Gyrification of the Mammalian Cerebellum

| PRJNA690106 | ENA

Zeb2 is Essential for Bergmann Glial Development and Cerebellar Organization

Project description:Cerebellar circuitry is critical for balance and motor control among a wide array of functions and largely consists of granule and Purkinje neurons. Bergmann glia in the cerebellum form distinct morphological structures that facilitate granule neuron migration during development and that maintain the cerebellar organization and functional integrity. At present, molecular control of the formation and morphogenesis of Bergmann glia remains obscure. In this study, we found that Zeb2 (a.k.a. Sip1 or Zfhx1b), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly restricted to Bergmann glia and is essential for their development and maturation. The mice with Zeb2 ablation in the cerebellar neural progenitor exhibit dysgenesis of cerebellar cortical lamination and locomotion defects. Deletion of Zeb2 markedly reduced Bergmann glial proliferation, differentiation and the establishment of the normal radial scaffold, disrupting migration of granule cell progenitors from external to internal granular layers. Transcriptome profiling indicated that Zeb2 regulates multiple pathways including FGF and Notch signaling as well as axonal guidance cues including Netrin G2 and Gdf10 to control Bergmann glial development. Our data reveal that Zeb2 acts as a transcriptional integrator of diverse signaling pathways to regulate the formation and morphogenesis of Bergmann glia ensuring maintenance of cerebellar integrity, suggesting that Zeb2 dysfunction in Bergmann glia might contribute to motor deficits in Mowat-Wilson syndrome.

2018-06-25 | GSE84098 | GEO

The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain

Project description:Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional knockout of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal mouse brain. In laser capture microdissection followed by RNASeq, designed to profile gene expression specifically in the external granule layer (EGL) of the cerebellum, we find that SnoN promotes the expression of cell proliferation genes and concomitantly represses differentiation genes in granule neuron precursors in vivo. Remarkably, bioinformatics analyses reveal that SnoN-regulated genes contain binding sites for the transcription factors N-myc and Pax6, which promote the proliferation and differentiation of granule neuron precursors, respectively. Accordingly, we uncover novel physical interactions of SnoN with N-myc and Pax6 in cells. In behavior analyses, conditional knockout of SnoN impairs cerebellar-dependent learning in a delayed eye-blink conditioning paradigm, suggesting that SnoN-regulation of granule neuron precursor proliferation bears functional consequences at the organismal level. Our findings define a novel function and mechanism for the major transcriptional regulator SnoN in the control of granule neuron precursor proliferation in the mammalian brain.

2018-12-10 | GSE120278 | GEO

The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain

2018-12-10 | GSE120276 | GEO

Gene expression data from mouse cerebellar tumor samples

Project description:Gene expression data from mouse cerebellar tumors generated using CRISPR/Cas9 technology to disrupt Ptch1 and Chd7 in the embryonic cerebellum of Chd7 fl/+ mice by in utero electroporation.

2018-08-24 | GSE72331 | GEO

Genome-wide mapping of chromatin landscape in cerebellar granule cells

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

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

Project description:Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals, and cell types make the cerebellum an excellent model for addressing the critical function of polarity complex proteins in the generation and organization of neural tissues. Deleting apical polarity complex protein Pals1 in the developing cerebellum results in a remarkably undersized cerebellum with disrupted layers in poorly formed folia and strikingly reduced granule cell production. We demonstrate that Pals1 is not only essential for cerebellum organogenesis, but also for preventing premature differentiation and thus maintaining progenitor pools in cerebellar germinal zones, including cerebellar granule neuron precursors (CGNP) in the external granule layer (EGL). In the Pals1 mutants, expression of genes that regulate cell cycle were diminished, correlating with the loss of proliferating population of germinal zones. Furthermore, enhanced Shh signaling through activated Smoothened (Smo) cannot overcome impaired cerebellar cell generation, arguing for an epistatic role of Pals1 in proliferation capacity. Our study identifies Pals1 as a new intrinsic factor that regulates the generation of cerebellar cells and Pals1 deficiency as a potential inhibitor of overactive mitogenic signaling. Two groups of samples are included: mRNA obtained from 4 WT and 4 CKO animals at E17.5. hGFAP-Cre mice was used to delete Pals1 from most cerebellar neurons and glia (termed Pals1 CKO). Pals1fl/fl and hGFAP-Cre (Zhuo et al., 2001) were bred for generation of CKO.

2016-06-30 | E-GEOD-75696 | biostudies-arrayexpress

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

2016-06-30 | GSE75696 | GEO

CHD7 functions upstream of the retinoic acid synthetase ALDH1A3 to regulate inner ear development

Project description:CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant condition characterized by variably penetrant abnormalities in craniofacial, cardiac, and neuronal tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, up- or down-regulation of retinoic acid (RA) signaling during embryogenesis leads to developmental defects similar to those in CHARGE syndrome, suggesting CHD7 and RA share target genes or signaling pathways. Here, we report that CHD7 and retinoic acid receptor (RAR) do not directly interact, and that RA induces rapid neuronal differentiation of human SH-SY5Y neuroblastoma cells without affecting CHD7 levels. Instead, we provide evidence that CHD7 directly regulates expression of Aldh1a3, which encodes an RA synthetic enzyme, and that loss of Aldh1a3 partially rescues Chd7-mutant mouse inner ear defects, indicating that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development.

2020-08-30 | GSE103288 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data