RT Journal Article
SR Electronic
T1 Differential chromatin accessibility landscape of gain-of-function mutant p53 tumours
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.24.395913
DO 10.1101/2020.11.24.395913
A1 Bhavya Dhaka
A1 Radhakrishnan Sabarinathan
YR 2020
UL http://biorxiv.org/content/early/2020/11/24/2020.11.24.395913.abstract
AB Mutations in TP53 not only affect its tumour suppressor activity but also exerts oncogenic gain-of-function activity. While the genome-wide mutant p53 binding sites have been identified in cancer cell lines, the chromatin accessibility landscape driven by mutant p53 in primary tumours is unknown. Here, we leveraged the chromatin accessibility data of primary tumours from TCGA to identify differentially accessible regions in mutant p53 tumours compared to wild p53 tumours, especially in breast and colon cancers. We found 1587 lost and 984 gained accessible regions in breast, and 1143 lost and 640 gained regions in colon. However, less than half of those regions in both cancer types contain sequence motifs for wild-type or mutant p53 binding. Whereas, the remaining showed enrichment for master transcriptional regulators, such as FOX-Family TFs and NF-kB in lost and SMAD and KLF TFs in gained regions of breast. In colon, ATF3 and FOS/JUN TFs were enriched in lost, and CDX family TFs and HNF4A in gained regions. By integrating the gene expression data, we identified known and novel target genes regulated by the mutant p53. Together, these results suggest the tissue- and tumour-type specific role of mutant p53 in regulating chromatin structure and gene expression.Competing Interest StatementThe authors have declared no competing interest.Mutant p53TP53 gene with a hotspot (missense) mutation in the DNA-binding domainWild p53TP53 gene with no protein-affecting mutations and copy number alterationsLost peaks/regionPeak/region where chromatin accessibility has decreased in mutant p53 samples with respect to wild p53 samplesGain peaks/regionPeak/region where chromatin accessibility has increased in mutant p53 samples with respect to wild p53 samplesGOFGain of FunctionFDRFalse discovery rateCNACopy Number Alterationsp53 REpredicted p53 Response ElementTFTranscription Factor