KM mutant highlights enhancers in minor ZGA

Abstract

Before the first cell division, a fertilized embryo, also known as a zygote, contains 2 distinct nuclei called the paternal and maternal pronucleus (PN). During the zygotic period, the paternal PN undergoes massive epigenetic reprogramming characterized by removing protamines and establishing new epigenetic marks to acquire totipotency, whereas the epigenetic alteration of maternal PN is less dynamic. Reflecting this difference, the timing and levels of global gene transcription in the zygotic stage, called “minor zygotic gene activation (ZGA),” differ between paternal and maternal PNs,1 suggesting that the mechanism of transcriptional regulation is asymmetric. Consistent with this idea, several epigenetic events occur uniquely in each PN. For instance, H3.3, an H3 variant that is incorporated into chromatin independently of DNA replication, is the best characterized in zygotes due to its preferential incorporation into paternal chromatin soon after fertilization. A few studies have demonstrated the critical role of H3.3 methylation in early embryonic development by overexpressing the lysine-arginine (K-R) substitutions: e.g., H3.3-K27R and H3.3-K36R, in which the 27th and 36th lysine residues (respectively) are not methylated.2,3 However, unlike in yeast, genetic disruption of specific lysine residues in mammalian histones is impractical, since they are multiply encoded in the genome.