Charting the regulatory landscape of TP53 on transposable elements in cancer [ATAC-seq]

Comprehensive profiling of transposable element (TE)-derived transcripts dynamics under the regulation of p53 provides valuable resources for more clarity in p53 pleiotropic roles in cancer. In this project, we created three cancer cell lines with p53 genetic status as the only variable and used long-read RNA-seq to profile TE and TE-derived transcripts’ regulatory dynamics. By using both short-read RNA-seq and long-read RNA-seq, novel TE-derived transcripts as a function of p53 status were accurately profiled for the first time. We identified in total 2503 transcripts that use TE as potential promoters, among which, 141 to 210 are activated by p53 across three cancer cell lines. We found ERVs to serve as potential driving promoters, followed by LINEs. Epigenomic information from chromatin accessibility and DNA methylation provided additional support for active promoter potential for p53 upregulated TE-derived transcripts. Short-term restoration of p53 partially recovered chronic p53-regulated TE-derived transcriptional profile; whereas gain of function TP53 mutations, R175H and R273H, did not show evidence to act via TE network. Overall, in this paper, we provide a controlled isogenic cancer cell line system with TP53 mutation status as the only genetic variable, deliver a high confidence TE and TE-derived transcript atlas, and comprehensively identify active TE promoters that are direct and indirect targets of p53.