Genomics

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Direct interaction of MYCN and p53 regulate transcriptional responses in neuroblastoma [ChIP-Seq]


ABSTRACT: The net transcriptome of a cancer cell is defined by relative levels of transcription factors, activators, suppressors and co-factors. These in turn are controlled by epigenetic, genetic and metabolic restraints. Here we used RNA-Seq, ChIP-qPCR, and ChIP-Seq to determine the impact of MYCN protein levels on p53 and MYCN mediated transcription in neuroblastoma, a p53 wild-type neural crest derived pediatric malignancy. Of note, about 25% of neuroblastoma is MYCN amplified and expresses 10-100 fold higher levels of MYCN protein than non-amplified tumors. We hypothesized that p53 functions would be globally altered by extreme MYCN levels and this could help to explain aggressive biology and poor long term survival which distinguishes MYCN-amplified neuroblastoma. In fact, we found that in the context of high MYCN levels, activation of p53 results in marked changes in transcription of specific p53 and MYCN target loci regulating apoptosis, DNA repair and cell cycle progression. Co-immunoprecipitation of endogenous and GST-fused proteins, as well as ChIP-qPCR confirms formation of p53/MYCN complexes and enrichment of both transcription factors at active loci. This p53/MYC interaction is independent of MYC/MAX complexes. Together, these data demonstrate MYCN to be a direct co-factor modulating p53 transcriptional output in MYCN amplified cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83317 | GEO | 2018/05/17

REPOSITORIES: GEO

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