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CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis [ATAC-seq]

ABSTRACT: Cell-lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage- and developmental stage-specific transcriptional programs. Accessibility and inaccessibility of gene loci are controlled dynamically during cellular development. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in early B cell progenitors in vivo, B cell progenitors are arrested at an early pro-B-like stage of development, unresponsive to IL-7 receptor signaling and complete V(D)J rearrangements at Igh loci inefficiently. Importantly, CHD4-deficient B cells express a significant number of non-B cell lineage genes, including genes involved in the development of other hematopoietic lineages and neuronal cells. The absence of CHD4 increased chromatin accessibility at hundreds of these gene loci, suggesting that its ability to repress transcription by mobilizing nucleosomes and compacting chromatin is a barrier against inappropriate transcription. Together, our data demonstrate the importance of CHD4 in establishing and maintaining an appropriate transcriptome in early B lymphopoiesis via chromatin accessibility.

ORGANISM(S): Mus musculus

PROVIDER: GSE123503 | GEO | 2019/04/30

REPOSITORIES: GEO

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CHD4 is essential for transcriptional repression and lineage progression in B lymphopoiesis [RNA-seq]

Project description:Cell-lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage- and developmental stage-specific transcriptional programs. Accessibility and inaccessibility of gene loci are controlled dynamically during cellular development. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in early B cell progenitors in vivo, B cell progenitors are arrested at an early pro-B-like stage of development, unresponsive to IL-7 receptor signaling and complete V(D)J rearrangements at Igh loci inefficiently. Importantly, CHD4-deficient B cells express a significant number of non-B cell lineage genes, including genes involved in the development of other hematopoietic lineages and neuronal cells. The absence of CHD4 increased chromatin accessibility at hundreds of these gene loci, suggesting that its ability to repress transcription by mobilizing nucleosomes and compacting chromatin is a barrier against inappropriate transcription. Together, our data demonstrate the importance of CHD4 in establishing and maintaining an appropriate transcriptome in early B lymphopoiesis via chromatin accessibility.

2019-04-30 | GSE123502 | GEO

Chromodomain Helicase DNA-binding 4 (CHD4) is required for B cell identity and lineage progression

Project description:B cell specification and identity are controlled by transcription factors and cytokine receptors that drive the expression of stage-specific transcriptomes during lineage progression. A key feature of these mechanisms is the repression of inappropriate transcription. Here, we utilized RNA-seq to demonstrate that chromodomain helicase DNA-binding protein 4 (CHD4), an ATPase/helicase subunit of Mi-2/NuRD chromatin remodeling complexes, is essential for B cell identity. In mice that lack CHD4 selectively in the B lineage, defects include developmental arrest at the early pro-B cell stage. While many pro-B-specific genes are expressed in the mutant cells, transcripts that are normally restricted to other tissues including pancreas and bone are expressed out of context. Moreover, CHD4-deficient pro-B cells do not proliferate in response to IL-7, exhibit greatly decreased utilization of distal VH segments and accumulate DNA damage. Together, our data confirm the importance of CHD4 and NuRD complexes for the generation of functional B cells.

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The nucleosome remodeling and deacetylase complex protein CHD4 regulates neural differentiation of mouse embryonic stem cells by down-regulating p53

Project description:Lineage specification of the three germ layers occurs during early embryogenesis and is critical for normal development. The nucleosome remodeling and deacetylase (NuRD) complex is a repressive chromatin modifier that plays a role in lineage commitment. However, the role of chromodomain helicase DNA-binding protein 4 (CHD4), one of the core subunits of the NuRD complex, in neural lineage commitment is poorly understood. Here, we report that the CHD4/NuRD complex plays a critical role in neural differentiation of mouse embryonic stem cells (ESCs). We found that RNAi-mediated Chd4 knockdown suppresses neural differentiation, as did knockdown of methyl-CpG binding domain protein Mbd3, another NuRD subunit. Chd4 and Mbd3 knockdowns similarly affected changes in global gene expression during neural differentiation and up-regulated several mesendodermal genes. However, inhibition of mesendodermal genes by knocking out the master regulators of mesendodemal lineages, Brachyury and Eomes, through a CRISPR/Cas9 approach could not restore the impaired neural differentiation caused by the Chd4 knockdown, suggesting that CHD4 controls neural differentiation not by repressing other lineage differentiation processes. Notably, Chd4 knockdown increased the acetylation levels of p53, resulted in increased protein levels of p53. Double knockdown of Chd4 and p53 restored the neural differentiation rate. Furthermore, overexpression of BCL2, a downstream factor of p53, partially rescued the impaired neural differentiation caused by the Chd4 knockdown. Our findings reveal that the CHD4/NuRD complex regulates neural differentiation of ESCs by down-regulating p53.

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The landscape of accessible chromatin in mammalian pre-implantation embryos

Project description:In mammals, extensive chromatin reorganization is essential for reprogramming terminally committed gametes to a totipotent state during preimplantation development. However, the global chromatin landscape and its dynamics in this period remain unexplored. Here we report a genome-wide map of accessible chromatin in mouse preimplantation embryos using an improved assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) approach with CRISPR/Cas9-assisted mitochondrial DNA depletion. We show that despite extensive parental asymmetry in DNA methylomes, the chromatin accessibility between the parental genomes is globally comparable after major zygotic genome activation (ZGA). Accessible chromatin in early embryos is widely shaped by transposable elements and overlaps extensively with putative cis-regulatory sequences. Unexpectedly, accessible chromatin is also found near the transcription end sites of active genes. By integrating the maps of cis-regulatory elements and single-cell transcriptomes, we construct the regulatory network of early development, which helps to identify the key modulators for lineage specification. Finally, we find that the activities of cis-regulatory elements and their associated open chromatin diminished before major ZGA. Surprisingly, we observed many loci showing non-canonical, large open chromatin domains over the entire transcribed units in minor ZGA, supporting the presence of an unusually permissive chromatin state. Together, these data reveal a unique spatiotemporal chromatin configuration that accompanies early mammalian development. Refer to individual Series

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Distinct requirements of CHD4 during B cell development and antibody response

Project description:Immunoglobulin heavy chain (Igh) class switch recombination (CSR) requires B cell proliferation, germline transcription, AID-instigated generation of DNA double strand breaks and DNA end-joining. How these various DNA-protein interactions and DNA transactions at Igh occur within the context of the chromatin landscape are largely unknown. Histone post-translational modifications can modulate chromatin accessibility and one such epigenetic mark, H3K9me3 is present at activated Igh switch sequences that serve as recombination targets during CSR. The chromatin remodeling protein CHD4 binds H3K9me3 and shapes chromatin accessibility and gene expression in various cell types, but its role in B cell biology is yet to be elucidated. Here, we conditionally ablated CHD4 expression in different stages of B cell development. We find that while CHD4 is essential for early B cell development, it is dispensable for homeostatic maintenance of mature naïve B cells and differentiation into antigen-specific early memory B cells and plasmablasts. However, loss of CHD4 in activated B cells leads to a severe defect in CSR, accompanied by markedly impaired cellular proliferation. Conditional deletion of p53 rescued the proliferation defect but failed to restore CSR due to a failure of AID to be efficiently recruited to Igh. This work unmasks a context-dependent role of CHD4 in B cell development and identifies CHD4 as a novel effector of CSR that influences B cell proliferation and recruitment of AID to Igh.

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Project description:The Chd4 helicase regulates chromatin accessibility and gene expression critical for β-cell function in vivo.

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2016-06-15 | E-GEOD-66582 | biostudies-arrayexpress

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