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Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation [RNA-seq]

ABSTRACT: Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation [RNA-seq]

PROVIDER: PRJNA966984 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24416236.fastq.gz	Fastqsanger.gz
	SRR24416237.fastq.gz	Fastqsanger.gz
	SRR24416238.fastq.gz	Fastqsanger.gz
	SRR24416239.fastq.gz	Fastqsanger.gz
	SRR24416240.fastq.gz	Fastqsanger.gz

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Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation

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Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation [ChIP-seq]

Project description:Chromatin integrates extracellular signals to regulate gene expression and, therefore, tightly controls development. Mutations in histone genes, including H3.3 and H4, were recently identified in children with developmental disorders characterized by intellectual disability and dysmorphic facial features1–7. However, the mechanistic and functional roles of these de novo, heterozygous germline mutations remain largely unknown. Here, we focus on the histone H4 lysine 91 to arginine (H4K91R) or glutamine (H4K91Q) mutations located within the highly conserved core histone fold domain. Our findings demonstrate that H4K91 mutants form aberrant nuclear puncta in mouse embryonic stem cells (mESCs), as well as in differentiated neural cells in vitro and in vivo. Genome-wide analyses revealed that H4K91 mutants accumulate ectopically at H3.3 and H3K9me3-enriched heterochromatin regions. Mechanistically, H4K91 mutants demonstrated enhanced binding to histone H3 variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminished the formation of H4 mutant puncta and enrichment at heterochromatin regions. Additionally, H4 mutant expression increased chromatin accessibility in mammalian cells. Phenotypically, H4 mutant mice exhibit reduced brain size and altered cortical neuron layers, reminiscent of microcephaly phenotypes observed in patients. Consistent with the altered brain development in vivo, the expression of H4 mutants alter developmental gene expression and accelerate pro-neural differentiation in cell culture models. Together, these studies reveal multiple concurrent pathogenic mechanisms of H4 mutants found in developmental disorders and further our understanding of how histone mutants regulate cell fate during development.

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Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation [RNA-seq]

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Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation.

Project description:Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3.3, and ablation of H3.3 or the H3.3-specific chaperone DAXX diminishes the mutant localization to chromatin. Our functional studies demonstrate that H4K91 mutant expression increases chromatin accessibility, alters developmental gene expression through accelerating pro-neural differentiation, and causes reduced mouse brain size in vivo, reminiscent of the microcephaly phenotypes of patients. Together, our studies unveil a distinct molecular pathogenic mechanism from other known histone mutants, where H4K91 mutants misregulate cell fate during development through abnormal genomic localization.

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