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| 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
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| 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.
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| 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.
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| Contributor(s) |
Feng L, Barrows D, Carroll TS, Allis CD |
| Citation(s) |
37808786 |
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| Submission date |
May 03, 2023 |
| Last update date |
Oct 20, 2023 |
| Contact name |
Douglas Barrows |
| E-mail(s) |
dbarrows@rockefeller.edu
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| Phone |
7749940981
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| Organization name |
Rockefeller University
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| Street address |
1230 York Ave
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (36)
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| This SubSeries is part of SuperSeries: |
| GSE231567 |
Altered chromatin occupancy of patient-associated H4 mutants misregulate neuronal differentiation |
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| Relations |
| BioProject |
PRJNA967124 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE231566_RAW.tar |
9.5 Gb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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