H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes.

Polycomb group (PcG) and Trithorax group (TrxG) proteins establish bivalent chromatin marked by H3K27me3, H2AK119ub1, and H3K4me3. However, how bivalent chromatin is formed in vivo in mammals is poorly understood. In mouse oocytes, it arises at thousands of promoters, including noncanonical imprinted loci whose H3K27me3 is intergenerationally inherited by early embryos. Here, we show that H3K27me3 is deposited at H3K4me3-premarked promoters in an H2AK119ub1-dependent manner during oogenesis. We find that H2AK119ub1 deficiency causes transcriptional derepression and loss of H3K27me3 proportional to preexisting H3K4me3 levels in oocytes. Importantly, concomitant deficiency of H2AK119ub1 and MLL2-mediated H3K4me3 substantially restores transcriptional silencing and H3K27me3 deposition, leading to partial restoration of noncanonical imprinting in offspring. Taken together, we propose that H2AK119ub1 antagonizes MLL2 function to repress bivalent genes during oogenesis, thereby conferring heritable H3K27me3. This study reveals how PcG and TrxG counteraction shapes the maternal epigenome for the next generation's development.