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

Spontaneous or pharmacological loss of epigenetic repression exposes thousands of promoters encoded in transposable elements (TEs) for pervasive transcriptional activation. Despite the potential impact of TE de-repression on genome regulation, it remains unknown how TE responses vary between epigenetically targeted cancer cells and whether their de-repression is stochastic or co-regulated with genic transcriptional programs. Here, we develop an approach to quantify TE transcription initiation at single cell and locus resolution to link it with genic programs in epigenetically relaxed cancer cell populations. We find combinatorial TE expression patterns are associated with cell cycle stages, stress response signatures and immune response pathways. The data suggest single cell heterogeneity in TE expression is also driven by the diversity of epigenomic contexts and sequence polymorphisms within large TE families. Our approach thereby facilitates the identification of a previously underestimated source of regulatory heterogeneity in cells with relaxed epigenetic repression.