Programmed Double-stranded RNA Formation Enables Meiotic Stage Transitions

Abstract

Cell fate transitions rely on extensive transcriptional activation mediated by transcription factors, yet the equally important processes that ensure the selective removal of pre-existing mRNAs remain elusive. We uncover widespread formation of double-stranded RNA (dsRNA) during early-to-middle meiosis using quantitative RNA structure analysis, and validate hundreds of natural antisense transcripts (NATs) through long-read sequencing. These NATs are induced by meiosis-specific transcription factors, including Ndt80p, and pair with sense mRNAs to drive cytoplasmic aggregation of the resulting dsRNAs. These dsRNA aggregates are subsequently transported to the vacuole for clearance, likely via autophagy. This pathway selectively eliminates mRNAs before metaphase I, including NDJ1, which encodes a meiotic cohesion protein that would otherwise block chromosome segregation. Our study reveals a physiological role for large-scale dsRNA formation, and highlights a simple but powerful model: the same transcription factors that activate mRNAs required for a specific developmental stage also program the synthesis of NATs that promote removal of transcripts from the preceding stage, thereby driving bidirectional transcriptome reprogramming.