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Brain-specific deletion of histone variant H2A.z results in cortical neurogenesis defects and neurodevelopmental disorder

ABSTRACT: Brain-specific deletion of histone variant H2A.z results in cortical neurogenesis defects and neurodevelopmental disorder

PROVIDER: PRJNA417668 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6269040.fastq.gz	Fastqsanger.gz
	SRR6269041.fastq.gz	Fastqsanger.gz
	SRR6269042.fastq.gz	Fastqsanger.gz
	SRR6269043.fastq.gz	Fastqsanger.gz
	SRR6269044.fastq.gz	Fastqsanger.gz

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Brain-specific deletion of histone variant H2A.z results in cortical neurogenesis defects and neurodevelopmental disorder

Project description:ChIP experiment was performed with antibody against H3K36me3 (active motif; 61101). we generated genome-wide characterization of H3K36me3 occupancy in E13 H2A.Z cKO forebrain. We found H3K36me3 is decreased throughout the whole genome in E13 H2A.Z cKO forebrain.

2017-11-09 | GSE106679 | GEO

Brain-specific deletion of histone variant H2A.z results in cortical neurogenesis defects and neurodevelopmental disorder.

Project description:Defects in neurogenesis alter brain circuit formations and may lead to neurodevelopmental disorders such as autism and schizophrenia. Histone H2A.z, a variant of histone H2A, plays critical roles in chromatin structure and epigenetic regulation, but its function and mechanism in brain development remain largely unknown. Here, we find that the deletion of H2A.z results in enhanced proliferation of neural progenitors but reduced neuronal differentiation. In addition, neurons in H2A.z knockout mice exhibit abnormal dendrites during brain development. Furthermore, H2A.zcKO mice exhibit serial behavioral deficits, such as decreased exploratory activity and impaired learning and memory. Mechanistically, H2A.z regulates embryonic neurogenesis by targeting Nkx2-4 through interaction with Setd2, thereby promoting H3K36me3 modification to activate the transcription of Nkx2-4. Furthermore, enforced expression of Nkx2-4 can rescue the defective neurogenesis in the H2A.z-knockdown embryonic brain. Together, our findings implicate the epigenetic regulation by H2A.z in embryonic neurogenesis and provide a framework for understanding how disruption in the H2A.z gene may contribute to neurological disorders.

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Replacement of Arabidopsis H2A.Z with human H2A.Z orthologs reveals extensive functional conservation and limited importance of the N-terminal tail sequence for Arabidopsis development (WT, h2a.z, h2a.z + AtHTA11 RNA-Seq)

Project description:To investigate the functional conservation of H2A.Z histones during eukaryotic evolution we transformed h2a.z deficient plants with three human H2A.Z proteins to assess their ability to rescue the mutant defects. We discovered that human H2A.Z.1 and H2A.Z.2.1 fully complement the phenotypic abnormalities of h2a.z plants even though Arabidopsis and human H2A.Z N-terminal tail sequences are divergent, while the brain-specific splice variant H2A.Z.2.2 has a dominant-negative effect in wild-type plants. Furthermore, H2A.Z.1 almost completely re-establishes normal H2A.Z chromatin occupancy in h2a.z plants and restores the expression of more than 84 % of misexpressed genes. Finally, our hypothesis that the N-terminal tail of Arabidopsis H2A.Z is not crucial for its overall function was supported by the ability of N-terminal end truncations of Arabidopsis HTA11 to largely rescue the defects of h2a.z mutants.

2024-05-13 | GSE263310 | GEO

2024-05-13 | GSE263311 | GEO

Neurodevelopmental Defects in Human Cortical Organoids with N-acetylneuraminic Acid Synthase Mutation

Project description:Biallelic genetic variants in N-acetylneuraminic acid synthase (NANS), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we discovered that NANS mutation resulted in absence of both sialic acid and protein polysialylation in the cortical organoids and significantly reduced the proliferation and expansion of neural progenitors. NANS mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that NANS loss-of-function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, Nans heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking NANS mutation with its clinically relevant neurodevelopmental disorders.

2023-06-26 | GSE233460 | GEO

Mutations in distinct translation-dependent quality control pathways lead to convergent molecular pathogenesis and neurodevelopmental defects.

Project description:Translation-dependent quality control pathways govern protein synthesis and proteostasis by degrading potentially toxic peptide products derived from aberrant mRNAs. However, little is known about the in vivo defects that arise in the absence of these pathways and how translation is altered in the absence of these pathways. Here, we demonstrate that the ribosome rescue factors Pelo/Hbs1l are both critical for embryonic and neuronal development but dispensable for neuronal survival in the adult brain. Loss of Pelo/Hbs1l in cerebellar progenitors impaired differentiation of these cells. Our analysis of Pelo/Hbs1l deficient fibroblasts revealed translational reprogramming of multiple pathways including mTORC1 signaling likely to restore cellular homeostasis. Interestingly, similar affects on the translatome, signaling pathways and neurogenesis were observed when we conditionally deleted Upf2 to inhibit NMD. These data reveal that translation-dependent quality control pathways, which set out to mitigate errors in translation and to clear defective peptide products and aberrant mRNAs can trigger similar cellular responses and neurodevelopmental abnormalities.

2021-03-15 | GSE162556 | GEO

Neurodevelopmental Defects in Human Cortical Organoids with N-acetylneuraminic Acid Synthase Mutation

Project description:Neurodevelopmental Defects in Human Cortical Organoids with N-acetylneuraminic Acid Synthase Mutation

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A cancer-associated mutation in H2A.Z decreases nucleosome stability and impairs mitotic progression

Project description:The histone variant H2A.Z is one of the most evolutionally conserved histone variants. Here, we identified a cancer-associated mutation in H2A.Z and evaluate the mutation. Structural and biochemical in vitro analyses showed that the H2A.Z mutation destabilizes nucleosome containing it. Then we applied the genetic complementation analysis to analyze cellular functions of the H2A.Z mutant. Although the H2A.Z mutant is deposited into nucleosome and rescues the lethality of H2A.Z DKO cells, the mutant does not complement mitotic defects of H2A.Z DKO cells, suggesting that stability of H2A.Z nucleosome is required for proper mitotic progression. Importantly, the H2A.Z mutant led to mitotic defects even in the presence of a larger pool of wild-type H2A.Z. Thus, it is implicated that the cancer-associated mutation appeared in an allele of the H2A.Z isoform genes would be involved in carcinogenesis through causing mitotic defects.

2024-10-28 | GSE84647 | GEO

Association of HMG20A to H2A.Z, PWWP2A and NuRD complex

Project description:Specialized chromatin-binding proteins are required for DNA-based processes during development. We recently established PWWP2A as a direct histone variant H2A.Z interactor involved in mitosis and craniofacial development. Here, we identify the H2A.Z/PWWP2A-associated protein HMG20A as part of several chromatin-modifying complexes, including NuRD, andshow that it localizes to distinct genomic regulatory regions. Hmg20a depletion causes severe head and heart developmental defects in Xenopus laevis. Our data indicate that craniofacial malformations are caused by defects in neural crest cell (NCC) migration and cartilage formation. These developmental failures are phenocopied in Hmg20a-depleted mESCs, which show inefficient differentiation into NCCs and cardiomyocytes (CM). Consequently, loss of HMG20A, which marks open promoters and enhancers, results in chromatin accessibility changes and a striking deregulation of transcription programs involved in epithelial-mesenchymal transition (EMT) and differentiation processes. Collectively, our findings implicate HMG20A as part of the H2A.Z/PWWP2A/NuRD-axis and reveal it as a key modulator of intricate developmental transcription programs that guide the differentiation of NCCs and CMs.

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Replacement of Arabidopsis H2A.Z with human H2A.Z orthologs reveals extensive functional conservation and limited importance of the N-terminal tail sequence for Arabidopsis development (ChIP-Seq)

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