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Series GSE231566 Query DataSets for GSE231566
Status Public on Oct 19, 2023
Title Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation [ChIP-seq]
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary 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.
Overall design Characterization of the genome-wide incorporation of H4WT and H4K91 mutants in mouse embryonic stem cells (mESCs) as well as in differentiated neural cells.
Contributor(s) Feng L, Barrows D, Carroll TS, Allis CD
Citation(s) 37808786
Submission date May 03, 2023
Last update date Oct 20, 2023
Contact name Douglas Barrows
Phone 7749940981
Organization name Rockefeller University
Street address 1230 York Ave
City New York
State/province NY
ZIP/Postal code 10065
Country USA
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (36)
GSM7290866 HA_parental_EV_Input
GSM7290867 HA_parental_EV_ChIP
GSM7290868 HA_parental_H4WT_Input
This SubSeries is part of SuperSeries:
GSE231567 Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation
BioProject PRJNA967124

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Supplementary file Size Download File type/resource
GSE231566_RAW.tar 9.5 Gb (http)(custom) TAR (of BW, NARROWPEAK)
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Raw data are available in SRA
Processed data provided as supplementary file

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