LINE-1 locus transcription nucleates oncogenic chromatin architecture
Retrotransposons are a prolific class of genomic parasites frequently upregulated in human cancers, where their spontaneous mobility can generate insertional mutations and structural variations. However, whether retrotransposon-derived gene products contribute to cancer beyond retrotransposition remains unclear. Here, we identify an oncogenic, chromatin-associated function of RNAs produced by Long Interspersed Element-1 (LINE-1), the only autonomous human retrotransposon. Sequencing analysis of subcellular fractions revealed that LINE-1 RNAs primarily exist as nascent transcripts expressed from full-length, cell type-specific genomic copies of evolutionarily young LINE-1 subfamilies. Through developing a long-read sequencing-based chromosome conformation assay, we uncovered a class of highly interactive LINE-1 loci essential for gene expression across cancer subtypes, establishing an unexpected regulatory link between LINE-1 locus transcription and oncogenic gene expression via long-range chromatin interactions. Depleting LINE-1 RNAs disrupted LINE-1-centric chromatin interactions, leading to the downregulation of associated genes, whereas inserting a LINE-1 element into an endogenous genomic locus induced de novo chromatin interactions in a transcription-dependent manner. Therefore, retrotransposons not only mutagenize linear genetic content but also regulate cancer gene expression through transcription-dependent nucleation of chromatin architecture.