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

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 Bombyx silk gland and Drosophila 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.