Feedback regulation by antagonistic epigenetic factors potentially maintains developmental homeostasis in Drosophila

Drosophila Polycomb group (PcG) repressors confer epigenetically heritable silencing on key regulatory genes through histone H3 trimethylation on lysine 27 (H3K27me3). How the silencing state withstands antagonistic activities from co-expressed trithorax group (trxG) activators is unclear. Upon overexpression of Trx H3K4 methylase, to perturb the silenced state, we find a dynamic process triggered in a stepwise fashion to neutralize the inductive impacts from excess Trx. Shortly after Trx overexpression, there are global increases in H3K4 trimethylation and RNA polymerase II phosphorylation, marking active transcription. Subsequently, these patterns diminish at the same time as the levels of Set1, an abundant H3K4 methylase involved in productive transcription, reduce. Concomitantly, the global H3K27me3 level is markedly reduced, corresponding to an increase in the amount of Utx demethylase. Finally, excess Pc repressive complex 1 (PRC1) is induced and located to numerous ectopic chromosomal sites independently of H3K27me3 and several key recruitment factors. The observation that PRC1 becomes almost completely colocalized with Trx suggests new aspects of recruitment and antagonistic interaction. We propose that these events represent a feedback circuitry ensuring the stability of the silenced state.