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Chromatin Remodeling Inactivates Activity Genes and Regulates Neural Coding

ABSTRACT: Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating mRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE83253 | GEO | 2016/07/18

SECONDARY ACCESSION(S): PRJNA325442

REPOSITORIES: GEO

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Chromatin Remodeling Inactivates Activity Genes and Regulates Neural Coding

Project description:Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating mRNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain. One or two replicates of the histone modifications (H3K27me3 and H2A.z), total histone proteins (H2A.z and H3), and ATPase Chd4 using postnatal day 22 cerebella from wild type (WT) or Chd4 conditional knockout (cKO) mice were examined using libraries prepared with the Illumina ChIP-Seq DNA Sample Prep Kit. Four replicates of total RNA were extracted from postnatal day 27-28 cerebella from rotarod-trained or control homecage mice, or Chd4 cKO or WT mice using Trizol and reverse-transcribed with oligo-dT priming. Three replicates of immunoprecipitated Sync-TRAP RNA or the input control using postnatal day 12 Chd4 cKO or WT cerebella were purified and amplified with Ovation RNA-Seq System V2 (NuGEN). All samples were sequenced on the Illumina HiSeq 2000 platform.

2016-07-18 | E-GEOD-83253 | biostudies-arrayexpress

Promoter Decommissioning by the NuRD Chromatin Remodeling Complex Triggers Synaptic Connectivity in the Mammalian Brain

Project description:Precise control of gene expression plays fundamental roles in brain development, but the roles of chromatin regulators in neuronal connectivity have remained poorly understood. Here, we find that depletion of the nucleosome remodeling and deacetylation (NuRD) complex in the cerebellar cortex by in vivo RNAi in rats and conditional knockout of the core NuRD subunit Chd4 in mice profoundly impairs the establishment of granule neuron parallel fiber/Purkinje cell synapses. In RNA-Seq analyses of Chd4 conditional knockout mice, we identify a set of nearly 200 genes that are repressed by the NuRD complex in the cerebellum in vivo. Genome-wide ChIP-Seq analyses reveal that the NuRD complex selectively decommissions the promoters of NuRD-repressed genes in the cerebellum in vivo by inducing the deacetylation of histone H3K9/14 and H3K27 and demethylation of H3K4 at these genes. Importantly, temporal control of promoter decommissioning and repression of NuRD target genes upon maturation of the cerebellum requires the NuRD complex. Finally, in a targeted in vivo RNAi screen of NuRD-repressed target genes, we identify the transcription factor Nhlh1, the RNA-binding protein Elavl2, and the presynaptic regulator Cplx3 as negative regulators of presynaptic differentiation in the cerebellar cortex. Together, these findings define NuRD-dependent promoter decommissioning as a developmentally regulated programming mechanism that releases the brake on presynaptic differentiation and thereby drives synaptic connectivity in the mammalian brain. Three distinct histone modifications using postnatal day 6 or day 22 cerebella from wild type (WT) or Chd4 conditional knockout (cKO) mice were examined in duplicate using libraries prepared with the Illumina ChIP-Seq DNA Sample Prep Kit and sequenced on the Illumina HiSeq 2000 platform.

2014-08-18 | E-GEOD-57758 | biostudies-arrayexpress

The NuRD chromatin remodelling complex regulates brain cortical development

Project description:Dynamic changes of histone epigenetic modifications and chromatin structure represent an universal mechanism by which cells adapt their transcriptional response to rapidly changing environmental conditions. During neuronal development, extensive chromatin remodeling takes place allowing the transition of pluripotent cells into differentiated neurons. Here we report that the ATP-dependent chromatin remodeling complex NuRD, which couples ATP-dependent nucleosome sliding with histone deacetylase activity, is a major remodeling complex in embryonic brain and plays an instructive role during mouse neuronal development. Importantly, the ATPase subunits of NuRD complex CHD3, CHD4 and CHD5 undergo a functional switch, thereby regulating distinct aspects of neuronal differentiation and migration in a sequential and mostly non-overlapping manner. We conclude that the recruitment of NuRD complexes containing specific CHDs to gene promoters and enhancers plays an instructive role in brain development. Gene expression analysis was performed in the mouse embryonic cortex at three developmental stages: E12.5, E15.5 and E18.5 using total RNA obtained from four embryos for each time point.

2015-06-27 | E-GEOD-70298 | biostudies-arrayexpress

Promoter Decommissioning by the NuRD Chromatin Remodeling Complex Triggers Synaptic Connectivity in the Mammalian Brain

2014-08-18 | GSE57758 | GEO

Transcription profiling of Drosophila mushroom body neurons

Project description:Genomic analysis of axon pruning in Drosophila mushroom body neurons identifies the RNA-binding protein Boule as a negative regulator; This SuperSeries is composed of the following subset Series:; GSE10012: Timecourse: MB neurons at the onset and early steps of axon pruning; GSE10013: EcR-dependent gene expression in MB neurons at the onset of axon pruning Experiment Overall Design: Refer to individual Series

2008-06-18 | E-GEOD-10014 | biostudies-arrayexpress

The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain

Project description:The development and function of the brain require tight control of gene expression. Genome architecture is thought to play a critical regulatory role in gene expression, but the mechanisms governing genome architecture in the brain in vivo remain poorly understood. Here, we report that conditional knockout of the chromatin remodeling enzyme Chd4 in granule neurons of the mouse cerebellum increases accessibility of gene regulatory sites genome-wide in vivo. Conditional knockout of Chd4 promotes recruitment of the architectural protein complex cohesin preferentially to gene enhancers in granule neurons in vivo. Importantly, in vivo profiling of genome architecture reveals that conditional knockout of Chd4 strengthens interactions among developmentally repressed contact domains as well as genomic loops in a manner that tightly correlates with increased accessibility, enhancer activity, and cohesin occupancy at these sites. Collectively, our findings define a role for chromatin remodeling in the control of genome architecture organization in the mammalian brain.

2020-04-13 | GSE138822 | GEO

Genome-wide analysis of gene expression in wild-type and Sp4 hypomorphic mouse cerebellum

Project description:Transcription factor Sp4 controls dendritic patterning during development of cerebellar granule neurons in culture by limiting branch formation and promoting activity-dependent pruning (Ramos et al., 2007). Sp4 is associated with neuropsychiatric disorders such as major depressive disorder, schizophrenia and bipolar disorder. In order to identify target genes of Sp4, we compared global gene expression in the cerebella of wild type and Sp4 hypomorph mice (Sp4neo-/-; Zhou et al, 2005). The results identify candidate Sp4 target genes that may contribute to neuronal development and neuropsychiatric disorders.

2014-11-27 | GSE53061 | GEO

Cdk5 regulates activity-dependent gene expression and dendrite development [cultured cortical neurons]

Project description:To investigate the molecular mechanism underlying activity-dependent dendrite development regulated by Cdk5, an unbiased microarray analysis was performed to identify activity-dependent genes differentially regulated in cortical neurons from E18 Cdk5-knockout embryos.

2015-12-11 | GSE68320 | GEO

CHD4 regulates super-enhancer accessibility in fusion-positive rhabdomyosarcoma and is essential for tumor growth

Project description:ATP-dependent chromatin remodelers modulate gene expression by regulating genome accessibility and can contribute to tumorigenesis. In fusion-positive rhabdomyosarcoma (FP-RMS), we have previously identified the chromatin remodeler and NuRD subunit CHD4 as an essential gene for tumor survival. Here, we demonstrate that the FP-RMS vulnerability to CHD4 goes beyond its function as a NuRD member. Mechanistically, CHD4 interacts with BRD4 and co-localizes with the tumor driver and fusion protein PAX3-FOXO1 at super-enhancers where it generates a chromatin architecture permissive for the binding of the fusion protein. This allows the positioning of RNA polymerase 2 at promoters and the expression of the oncogenic program of PAX3-FOXO1. Additionally, analysis of genome-wide cancer dependency databases identifies CHD4 amongst the NuRD subunits as general novel cancer vulnerability. Our findings describe, for the first time, CHD4 as a regulator of super-enhancer-mediated gene expression and establish this chromatin remodeler as an unexpected broad tumor susceptibility.

2019-12-20 | GSE140115 | GEO

NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency

2020-08-08 | GSE155861 | GEO

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