Massey Documents by Type

Permanent URI for this communityhttps://mro.massey.ac.nz/handle/10179/294

Browse

Subject: search.filters.subject.Histones

Search Results

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    EP400NL is involved in PD-L1 gene activation by forming a transcriptional coactivator complex
    (Elsevier B V, 2023-03) Li Z; Kim H; Kim J; Park JH
    EP400 is an ATP-dependent chromatin remodelling enzyme that regulates DNA double-strand break repair and transcription, including cMyc-dependent gene expression. We previously showed that the N-terminal domain of EP400 increases the efficacy of chemotherapeutic drugs against cancer cells. As the EP400 N-terminal-Like (EP400NL) gene resides next to the EP400 gene locus, this prompted us to investigate whether EP400NL plays a similar role in transcriptional regulation to the full-length EP400 protein. We found that EP400NL forms a human NuA4-like chromatin remodelling complex that lacks both the TIP60 histone acetyltransferase and EP400 ATPase. However, this EP400NL complex displays H2A.Z deposition activity on a chromatin template comparable to the human NuA4 complex, suggesting another associated ATPase such as BRG1 or RuvBL1/RuvBL2 catalyses the reaction. We demonstrated that the transcriptional coactivator function of EP400NL is required for serum and IFNγ-induced PD-L1 gene activation. Furthermore, transcriptome analysis indicates that EP400NL contributes to cMyc-responsive mitochondrial biogenesis. Taken together, our studies show that EP400NL plays a role as a transcription coactivator of PD-L1 gene regulation and provides a potential target to modulate cMyc functions in cancer therapy.
  • Thumbnail Image
    Item
    Allele-specific binding variants causing ChIP-seq peak height of histone modification are not enriched in expression QTL annotations.
    (BioMed Central Ltd, 2024-06-27) Ghoreishifar M; Chamberlain AJ; Xiang R; Prowse-Wilkins CP; Lopdell TJ; Littlejohn MD; Pryce JE; Goddard ME
    BACKGROUND: Genome sequence variants affecting complex traits (quantitative trait loci, QTL) are enriched in functional regions of the genome, such as those marked by certain histone modifications. These variants are believed to influence gene expression. However, due to the linkage disequilibrium among nearby variants, pinpointing the precise location of QTL is challenging. We aimed to identify allele-specific binding (ASB) QTL (asbQTL) that cause variation in the level of histone modification, as measured by the height of peaks assayed by ChIP-seq (chromatin immunoprecipitation sequencing). We identified DNA sequences that predict the difference between alleles in ChIP-seq peak height in H3K4me3 and H3K27ac histone modifications in the mammary glands of cows. RESULTS: We used a gapped k-mer support vector machine, a novel best linear unbiased prediction model, and a multiple linear regression model that combines the other two approaches to predict variant impacts on peak height. For each method, a subset of 1000 sites with the highest magnitude of predicted ASB was considered as candidate asbQTL. The accuracy of this prediction was measured by the proportion where the predicted direction matched the observed direction. Prediction accuracy ranged between 0.59 and 0.74, suggesting that these 1000 sites are enriched for asbQTL. Using independent data, we investigated functional enrichment in the candidate asbQTL set and three control groups, including non-causal ASB sites, non-ASB variants under a peak, and SNPs (single nucleotide polymorphisms) not under a peak. For H3K4me3, a higher proportion of the candidate asbQTL were confirmed as ASB when compared to the non-causal ASB sites (P < 0.01). However, these candidate asbQTL did not enrich for the other annotations, including expression QTL (eQTL), allele-specific expression QTL (aseQTL) and sites conserved across mammals (P > 0.05). CONCLUSIONS: We identified putatively causal sites for asbQTL using the DNA sequence surrounding these sites. Our results suggest that many sites influencing histone modifications may not directly affect gene expression. However, it is important to acknowledge that distinguishing between putative causal ASB sites and other non-causal ASB sites in high linkage disequilibrium with the causal sites regarding their impact on gene expression may be challenging due to limitations in statistical power.
  • Thumbnail Image
    Item
    Histone H1 phosphorylation during mitosis : a dissertation presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatū, New Zealand
    (Massey University, 2016) Bond, Sarah D
    Histone H1 phosphorylation is important for the regulation of high order chromosome organisation during mitosis. One of these phosphorylation sites in the linker histone subtype H1.4 is shown here to be phosphorylated by Aurora B kinase, a master regulator of mitosis. Altered phosphorylation of H1.4 on this phosphorylation site at serine 27 illustrated the significance of the timing of this phosphorylation. When serine 27 of H1.4 is mutated to prevent this phosphorylation chromosome congression to the equatorial plate during metaphase is hindered. In contrast, in the presence of the constitutive H1.4 serine 27 phosphorylation mimic, bridging and lagging chromosomes occurred, leading to a corresponding increase in the proportion of cells with a micronucleus. These phenotypes could be brought about through disruption of the Heterochromatin protein 1 family members bound to the adjacent methylated lysine. Such aberrations during mitosis can lead to genetic instability and ultimately aneuploidy, a hallmark of cancer. With the frequently reported over-expression of Aurora B in cancer this shows another mechanism in which this kinase, via histone H1.4 phosphorylation, can push a cell toward malignancy. Another important mitotic kinase, Cyclin dependent kinase 1 together with cyclin B, is responsible for the hyperphosphorylation of histone H1.4 during mitosis; which is required for condensing the cells genetic information into highly compact metaphase chromosomes. This vital mitotic event ensures the faithful transmission of the duplicated DNA into the dividing daughter cells. The mechanisms through which histone H1 hyperphosphorylation contribute to chromosome condensation are poorly understood. One mechanism through which this may occur is via the recruitment of condensation factors such as the condensins or Topoisomerase II. Here the interaction between the Condensin I subunit, CAPD2, and histone H1.4 is explored. CAPD2 interacts with the two most prominent linker histone subtypes, H1.4 and H1.2, through their C-terminal tails. H1.4 and CAPD2 can interact in vitro whilst each is phosphorylated by cyclin dependent kinase as they are during mitosis, in a manner dependent on RNA. Overall, these results indicate that histone H1.4 is a vital component of higher order chromatin and its phosphorylation is essential for the normal progression through mitosis.