Retrotransposon-driven co-transcriptional chromatin remodelling rewires Ash2l isoform usage to prime developmental promoters [ChIP-seq]

Here, we show that the chromatin regulator ASH2L undergoes developmentally regulated alternative TSS switching in differentiating mouse cells, generating distinct mRNA and protein isoforms: a full-length ASH2L and a truncated form lacking an intrinsically disordered region (IDR).

In pluripotent stem cells, transcription from the upstream TSS is driven by a mouse-specific retrotransposon element that suppresses transcription from the downstream TSS through a transcription interference mechanism involving SETD2-directed histone H3 lysine 36 methylation. The resulting upstream-driven, stem cell–specific truncated ASH2L isoform primes developmental-gene promoters for histone H3 lysine 4 methylation, establishing a chromatin state required for embryogenesis and motor neuron differentiation.