Single cell analysis reveals dynamics of transposable element expression following epigenetic de-repression

De-repression of transposable elements (TEs) occurs concomitantly with the progressive loss of DNA methylation during carcinogenesis. The activation of promoters within high copy number TE families can thereby massively remodel the transcriptional and epigenetic state of cancer cells. This effect is accelerated following epigenetic therapy. However, whether TE de-repression is purely stochastic or co-regulated with genic transcriptional programs is poorly understood. Using single cell 5' RNA-sequencing, we characterize over ten-fold variation in global TE expression per single cancer cell following epigenetic therapy . We uncover combinatorial TE expression patterns across thousands of transcribed TE loci from hundreds of conserved families. These signatures are associated with distinct cell cycle stages, stress responses and additional gene regulatory processes. We finally exemplify how sequence composition and epigenomic context cooperate to shape the dynamic transcriptional landscape of large TE families.. Single cell RNA-sequencing thereby implicates thousands of potent promoters within TEs as an underestimated source of regulatory heterogeneity in cancer. Overall design: 5' single-cell RNA-seq of H1299 and HCT116 cells treated with a DNMT and HDAC inhibitor