Differential expression of H3.3 genes and their role in modulating temperature stress response in Caenorhabditis elegans
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE106889 | GEO | 2018/04/19
REPOSITORIES: GEO
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Project description:Periodic starvation of animals induces large shifts in metabolism, but may also influence many other cellular systems and can lead to adaption to prolonged starvation conditions. To date, there is limited understanding of how starvation affects gene expression, particularly at the protein level. Here, we have used mass spectrometry‐based quantitative proteomics to identify global changes in the C. elegans proteome due to acute starvation of young adult animals. Measuring changes in abundance of up to 7,000 proteins, we show that acute starvation rapidly alters the levels of hundreds of proteins, many involved in central metabolic pathways, highlighting key regulatory responses. Surprisingly, we also detect changes in the abundance of chromatin‐associated proteins including specific linker histones, histone variants and histone post‐translational modifications associated with the epigenetic control of gene expression. A null mutant for one of these proteins, the histone H3.3 variant HIS‐71, identified a subset of proteins whose abundance no longer varied in response to starvation. This mutant also displayed defects in starvation stress resistance and showed a reduced adult lifespan. To maximise community access to these data, they are presented in an online searchable database, the Encyclopedia of Proteome Dynamics (http://www.peptracker.com/epd/).
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Project description:Histone variants can effect nucleosome stability or affect histone of DNA modifications. H3.3 is a major H3 histone variant that is incorporated into chromatin outside of S-phase in various eukaryotes. In animals, H3.3 is associated with active transcription and possibly maintenance of transcriptional memory. Plant H3.3, which evolved independently of animal H3.3, is much less well understood. We performed ChIP-chip using chromatin from rosette leaves of 35S:H3.3-YFP plants.
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Project description:This SuperSeries is composed of the following subset Series: GSE16882: Histone H1 binding is restricted by histone variant H3.3 (Nucleosome) GSE16883: Histone H1 binding is restricted by histone variant H3.3 (DamID) GSE16884: Histone H1 binding is restricted by histone variant H3.3 (Expression) GSE19764: Histone H1 binding is restricted by histone variant H3.3 (FAIRE) Refer to individual Series
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Project description:The incorporation of histone H3 variants has been implicated in the epigenetic memory of cellular state. Using genome editing with zinc finger nucleases to tag endogenous H3.3, we report genome-wide profiles of H3 variants in mammalian embryonic stem (ES) cells and neuronal precursor cells. Genome-wide patterns of H3.3 are dependent on amino acid sequence, and change with cellular differentiation at developmentally regulated loci. The H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes. Strikingly, Hira is not essential for localization of H3.3 at telomeres and many transcription factor binding sites. Immunoaffinity purification and mass spectrometry reveal that the proteins Atrx and Daxx associate with H3.3 in a Hira-independent manner. Atrx is required for Hira-independent localization of H3.3 at telomeres, and for the repression of telomeric RNA. Our data demonstrate that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells. Crosslinking ChIP-seq: Examination of 1 histone variant (H3.3), 2 histone modifications, and Serine-5 phosphorylated RNA polymerase in 2 different cell types (H3.3-HA ES samples 1-4, and H3.3-HA NPC samples 7-10). Examination of 1 histone variant (H3.2), and one histone modification (H3K36me3) in 2 different cell types (H3.2-HA ES samples 5-6, and H3.2-HA NPC samples 11-12). Examination of 1 histone variant (H3.3), input control, and one histone modification (H3K36me3) in one cell type (H3.3-HA hybrid ES, samples 13-15). Examination of 1 histone variant (H3.1S31), input control, and one histone modification (H3K36me3) in one cell type (H3.1S31-HA hybrid ES, samples 16-18). Native ChIP-seq: Examination of 1 histone variant (H3.3), input control, and one histone modification (H3K4me3) in one cell type (H3.3-HA ES, samples 19-21). Examination of 1 histone variant (H3.2), input control, and two histone modifications (H3K4me3 and H3K27me3) in one cell type (H3.2-HA ES, samples 22-25). Examination of 1 histone variant (H3.3), input control, and two histone modifications (H3K4me1 and H3K36me3) in one cell type (H3.3-EYFP ES, samples 26-29). Examination of 1 histone variant (H3.3), input control, and two histone modifications (H3K4me1 and H3K36me3) in one cell type (Hira -/- H3.3-EYFP ES, samples 30-33). Examination of 1 histone variant (H3.3) and input control in one cell type (Atrxflox H3.3-EYFP ES, samples 34-37). Examination of HA antibody background in one cell type (wild-type ES, sample 38).
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Project description:Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme Polynucleotide Kinase 3'-Phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.
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Project description:Histone H3.3 is a highly conserved histone H3 replacement variant in metazoans, and has been implicated in many important biological processes including cell differentiation and reprogramming. Germline and somatic mutations in H3.3 genomic incorporation pathway components, or in H3.3 encoding genes, have been associated with human congenital diseases and cancers, respectively. However, the role of H3.3 in mammalian development remains unclear. To address this question, we generated H3.3 null mouse models through classical genetic approaches. We found H3.3 plays an essential role in mouse development. Complete depletion of H3.3 leads to developmental retardation and early embryonic lethality. At the cellular level, H3.3 loss triggers cell cycle suppression and cell death. Surprisingly, H3.3 depletion does not dramatically disrupt gene regulation in the developing embryo. Instead, H3.3 depletion causes dysfunction of heterochromatin structures at telomeres, centromeres and pericentromeric regions of chromosomes leading to mitotic defects. The resulting karyotypical abnormalities and DNA damage lead to p53 pathway activation. In summary, our results reveal that an important function of H3.3 is to support chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. RNA-seq in embryos at E10.5 comparing 3 samples with the following genotype Trp53-/-; H3f3afl/-; H3f3bfl/-; Sox2-CreTg/0 to three samples with the following genotype Trp53-/-; H3f3afl/+; H3f3bfl/+; Sox2-CreTg/0
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