Transcription factor Tono mediates histone H3K4 trimethylation to regulate endoreplication through transcriptional reprogramming.

Abstract

Endoreplication is a cell cycle variant that involves multiple rounds of DNA replication without cell division, resulting in enlarged cells and organs. Here, we combined the <i>Bombyx</i> silk gland and <i>Drosophila</i> salivary gland to determine the mechanism underlying transcriptional reprogramming during the mitotic-to-endoreplication transition. Transcriptome profiling of the silk gland revealed that genes involved in multiple processes, especially cell cycle control, growth, and morphogenesis, are up-regulated after endoreplication entry. We further found that global levels of histone H3K4 trimethylation (H3K4me3) in the silk gland increase following endoreplication entry; the depletion of the COMPASS H3K4 methyltransferase complex subunit Wds in the silk gland or salivary gland blocks endoreplication; and a subset of up-regulated genes are targeted and transcriptionally reprogrammed by H3K4me3. The transcription factor Tono mediates H3K4me3 deposition at target loci by recruiting the Wds-containing COMPASS complex, thereby promoting endoreplication. These findings reveal an epigenetic mechanism by which Tono orchestrates transcriptional reprogramming through the H3K4me3 modification to regulate endoreplication progression.