Locus-specific transcriptional regulation of transposable elements by p53

The tumor suppressor p53 protects genomic integrity in part by regulating transposable elements (TEs). Most studies of p53-TE interactions rely on synthetic DNA and reporter assays, which estimate expression only at the family or subfamily level and lack locus-specific resolution. To address this limitation, we developed a computational pipeline for ChIP-seq and RNA-seq analysis that employs advanced algorithms to accurately assign short reads mapping to multiple genomic locations. This approach enables precise quantification of TE transcripts at the locus level. By integrating p53 ChIP peaks with differentially expressed TE transcripts, we identified retroelements directly regulated by p53. Applying this framework to lung fibroblast IMR90 and colon cancer HCT116 cells treated with p53 activators, we observed a striking pattern: TEs were predominantly activated in normal IMR90 cells but repressed in HCT116 cancer cells. Analysis of 24 transcriptomes and 10 cistromes further confirmed this trend, distinguishing normal from cancer cell regulation. At the family level, normal cells showed broad TE upregulation, whereas cancer cells exhibited selective repression of Alu and LINE elements, with weaker effects on endogenous retroviruses. These findings provide the first comprehensive, locus-specific view of p53-mediated TE regulation, highlighting distinct chromatin-dependent dynamics in normal and cancer cells.