Transposable elements are co-opted as oncogenic regulatory elements by lineage-specific transcription factors in prostate cancer

Transposable elements hold regulatory functions to impact cell fate determination by controlling gene expression, which when altered can promote oncogenesis. Despite accounting for half of the human genome, little is known about the transcriptional mechanisms that confer regulatory properties to transposable elements in pluripotent, mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequence of H3K27ac ChIP-seq from 32 different normal cell and tissue states, we report pluripotent stem and mature cell states-specific “regulatory transposable elements”. Those specific to pluripotent stem cells are binding sites for the pluripotency factors NANOG, SOX2 and OCT4. In mature cell and tissue states, regulatory transposable elements are docking sites for lineage-specific transcription factors, such as AR and FOXA1 in benign prostate epithelium. Expanding the positional analysis to localized prostate tumors, we show how cancer cell states remaining dependent on AR share regulatory transposable elements with pluripotent stem cells. These include regulatory transposable elements, such as Tigger3a, that serve as binding sites for AR and whose regulatory functions are required for prostate cancer cell growth. Together, our results suggest that oncogenesis differs from normal cell fate determination by hijacking pluripotent stem cells regulatory transposable elements that serve as docking sites for lineage-specific transcription factors. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for H3K27ac and H3K9me3 in prostate cancer cell lines as well as RNA-seq and Cut&Run pull-downs for dCas9-KRAB H3K27ac or AR in clonal CRISPRi prostate cancer cells *** Submitter declares that raw data were not provided for some ChIP-seq samples dues to patient privacy concerns. ***