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Sex and mutation specific p53 gain-of-function activity in gliomagenesis [RNA-seq]

ABSTRACT: The goal of this study is to compare the sex specific effects of the expression of p53 missense mutations on the transcriptomes of male and female primary astrocytes. Primary cortical astrocytes harboring a single floxed Trp53 allele were harvested from male and female postnatal day one pups, and transduced with mutant p53;IRES GFP followed by CRE recombinase. mRNA was collected from male and female astrocytes transduce with mouse Trp53:R172H, Trp53:Y202C, or Trp53:Y217C. This study revealed sex specific gain-of-function effects on the transcriptomes of each cell line that correlated with cancer pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE188709 | GEO | 2021/11/16

REPOSITORIES: GEO

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Project description:TP53 mutations are frequent in esophageal squamous cell carcinoma (ESCC), and other SCCs, and are associated with a proclivity for metastasis. Here, we report that the Colony-Stimulating Factor-1 (CSF-1) expression is upregulated significantly in a p53-R175H (R172H in mice)-mediated manner in lung metastatic lesions of ESCC. The p53-R172H-dependent Csf-1 signaling through its cognate receptor Csf-1r increases tumor cell invasion and lung metastasis, which is mediated in part through the phosphorylation of Stat3 and epithelial-to-mesenchymal transition. In Trp53R172H tumor cells, p53 binds to the Csf-1 promoter and the Csf-1 locus is enriched with H3K27ac, which likely is permissive for fostering an interaction between Brd4 and p53-R172H to regulate the Csf-1 transcription. Inhibition of Brd4 not only reduces tumor invasion and lung metastasis but also reduces the Csf-1 level in circulation. Overall, our results establish that the p53-R175H-mediated Brd4-Csf-1 axis promotes ESCC lung metastasis and suggest avenues for therapeutic strategies for this difficult to treat disease. To elucidate the mechanism for how Trp53R172H regulates Csf-1 transcription, we conducted Cleavage Under Targets and Release Using Nuclease sequencing (CUT&RUN-seq) for histone 3 lysine 27 acetylation (H3K27ac), which is an active enhancer and promoter marker [48], on Trp53R172H/- or Trp53+/+ ESCC cells. The genome-wide analysis revealed 1189 genes having enriched and 1454 genes having depleted H3K27ac in Trp53R172H/- tumor cells compared to Trp53+/+ cells (|log2fold change| > 1.5). Notably, H3K27ac peaks were enriched across Vim gene encoding the mesenchymal marker Vimentin and were reduced across Cdh1 gene encoding the epithelial marker E- Cadherin in Trp53R172H tumor cells compared to Trp53+/+ cells. Interestingly, H3K27ac peaks were enriched across Csf-1 locus including the promoter site in Trp53R172H/- ESCC cells compared to Trp53+/+ tumor cells, suggesting that the Csf-1 locus was accessible and active in the presence of p53-R172H. The epigenetic reader Brd4 binds to acetylated histone lysine residues at promoters and super-enhancers to regulate transcription initiation [29]. We therefore investigated if Brd4 was recruited to enriched H3K27ac sites in ESCC cells to upregulate Csf-1. We found that global Brd4 level in Trp53R172H/- tumor cells was ~2-fold higher than in Trp53-/- cells and ~3-fold higher than in Trp53+/+ cells suggesting gain-of-function properties of p53-R172.

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Sex and mutation specific p53 gain-of-function activity in gliomagenesis [RNA-seq]

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