NuRD independent Mi2 activity represses ectopic gene expression during neuronal maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA818642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18430858_1.fastq.gz | Fastqsanger.gz | |||
| SRR18430858_2.fastq.gz | Fastqsanger.gz | |||
| SRR18430859_1.fastq.gz | Fastqsanger.gz | |||
| SRR18430859_2.fastq.gz | Fastqsanger.gz | |||
| SRR18430860_1.fastq.gz | Fastqsanger.gz |
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Project description:During neuronal development, extensive changes to chromatin states occur to regulate lineage-specific gene expression. The molecular factors underlying the repression of non-neuronal genes in differentiated neurons are poorly characterised. The Mi2/NuRD complex is a multiprotein complex with nucleosome remodelling and histone deacetylase activity. Whilst NuRD has previously been implicated in the development of nervous system tissues the precise nature of the gene expression programmes that it coordinates are ill-defined. Furthermore, evidence from several species suggests that Mi-2 may be incorporated into multiple complexes that may not incorporate histone deacetylase activity. Here, we show that Mi-2 activity is required for suppressing the ectopic expression of germline genes in neurons independently of HDAC1/NuRD, whilst components of the NuRD complex including Mi-2 regulate neural gene expression to ensure proper development of the larval nervous system. We find that Mi-2 and NuRD-associated repression of ectopic gene expression is restricted to the early stages of neuronal development, indicating that newly derived neurons are more sensitive to epigenetic perturbations.
2022-11-23 | GSE199146 | GEO
Project description:During neuronal development, extensive changes to chromatin states occur to regulate lineage-specific gene expression. The molecular factors underlying the repression of non-neuronal genes in differentiated neurons are poorly characterised. The Mi2/NuRD complex is a multiprotein complex with nucleosome remodelling and histone deacetylase activity. Whilst NuRD has previously been implicated in the development of nervous system tissues, the precise nature of the gene expression programmes that it coordinates is ill-defined. Furthermore, evidence from several species suggests that Mi-2 may be incorporated into multiple complexes that may not possess histone deacetylase activity. We show that Mi-2 activity is required for suppressing ectopic expression of germline genes in neurons independently of HDAC1/NuRD, whilst components of NuRD, including Mi-2, regulate neural gene expression to ensure proper development of the larval nervous system. We find that Mi-2 binding in the genome is dynamic during neuronal maturation, and Mi-2-mediated repression of ectopic gene expression is restricted to the early stages of neuronal development, indicating that Mi-2/NuRD is required for establishing stable neuronal transcriptomes during the early stages of neuronal differentiation.
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Project description:PWWP2A variant NuRD complex represses intragenic spurious transcription initiation
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Project description:RNAi knockdown of NURD subunits: MI2/CG8103, MEP1/CG1244, MTA1-like/CG2244; and TTK69 transcription factor
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Project description:The evolutionary conserved histone variant H2A.Z plays a crucial role in various DNA-based processes but the underlying mechanisms are not completely understood. Recently, we identified the zinc finger (ZNF) protein ZNF512B as an H2A.Z-, HMG20A- and PWWP2A-associated protein. Here, we report ZNF512B as a novel nucleosome remodeling and deacetylase (NuRD) complex binding protein. We discovered a conserved amino acid sequence within ZNF512B that resembles a NuRD-interaction domain (NIM) previously identified in FOG-1. By solving the crystal structure of this domain directly bound to the NuRD component RBBP4 and by applying several biochemical assays we demonstrate that this novel internal NIM sequence is both necessary and sufficient for high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as regulator (repressor) of gene expression, in both NuRD-dependent and -independent modes. Surprisingly, high levels of ZNF512B expression lead to concomitant nuclear protein and chromatin aggregation foci that form independent of the interaction with the NuRD complex but depend on ZNF512B’s zinc fingers. Our study has implications for diseases in which ZNF512B’s expression is deregulated, such as cancer and neurodegenerative diseases and reveal the existence of more proteins as potential NuRD interactors.
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Project description:H3 trimethylation at K36 deposited over the body of actively transcribed gene, is recognized by readers to modulate the epigenetic states, such as DNA methylation and histone deacetylation, to ensure the proper gene transcription. PWWP2A was identified as the reading component of variant NuRD complex to deacetylate gene bodies in mammalian cells. However, whether this deacetylation affects intragenic transcription is not investigated. Here, we performed CAGE-seq to profile transcription initiation in PWWP2A/B double knockout and fount that intragenic spurious transcription initiations at pre-existing low-level initiation from highly expressed genes were enhanced, accompanying with elevated acetylation level at H3K9 and H3K27, as well as nascent transcription. Additionally, the intragenic spurious transcriptions in PWWP2A/B loss are distinct with those in DNMT3B loss which is prone to produce de novo initiation and lack of PWWP2A/B-related chromatin changes. Collectively, PWWP2A/B-NuRD complex deacetylates active gene bodies to suppress intragenic spurious transcription in mammals.
2020-09-15 | GSE148382 | GEO
Project description:The evolutionary conserved histone variant H2A.Z plays a crucial role in various DNA-based processes but the underlying mechanisms are not completely understood. Recently, we identified the zinc finger (ZNF) protein ZNF512B as an H2A.Z-, HMG20A- and PWWP2A-associated protein. Here, we report ZNF512B as a novel nucleosome remodeling and deacetylase (NuRD) complex binding protein. We discovered a conserved amino acid sequence within ZNF512B that resembles a NuRD-interaction domain (NIM) previously identified in FOG-1. By solving the crystal structure of this domain directly bound to the NuRD component RBBP4 and by applying several biochemical assays we demonstrate that this novel internal NIM sequence is both necessary and sufficient for high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as regulator (repressor) of gene expression, in both NuRD-dependent and -independent modes. Surprisingly, high levels of ZNF512B expression lead to concomitant nuclear protein and chromatin aggregation foci that form independent of the interaction with the NuRD complex but depend on ZNF512B’s zinc fingers. Our study has implications for diseases in which ZNF512B’s expression is deregulated, such as cancer and neurodegenerative diseases and reveal the existence of more proteins as potential NuRD interactors.
2024-10-30 | PXD043366 | Pride
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.
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Project description:Molecular functions of the Nucleosome Remodeling and Deacetylation (NuRD) complex in the control of gene expression were investigated using an inducible system to direct its assembly in embryonic stem cells. This dataset profiles nascent RNA transcription in response to NuRD induction.
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