Trading Genome Vulnerability for Stable Genetic Inheritance: Active Retrotransposons Help Maintain Pericentromeric Heterochromatin Required for Faithful Cell Division

Abstract

Retrotransposons are extensively populated in vertebrate genomes, which, when active, are thought to cause genome instability with potential benefit to genome evolution. Retrotransposon-derived RNAs are also known to give rise to small endo-siRNAs to help maintain heterochromatin at their sites of transcription; however, as not all heterochromatic regions are equally active in transcription, it remains unclear how heterochromatin is maintained across the genome. Here, we attack these problems by defining the origins of repeat-derived RNAs and their specific chromatin registers in Drosophila S2 cells. We demonstrate that repeat RNAs are predominantly derived from active Gypsy elements, and upon their processing by Dicer-2, these endo-siRNAs act in cis and trans to help maintain pericentromeric heterochromatin. Remarkably, we show that synthetic repeat-derived siRNAs are sufficient to rescue Dicer-2 deficiency-induced defects in heterochromatin formation in interphase and chromosome segregation during mitosis, thus demonstrating that active retrotransposons are actually required for stable genetic inheritance.