Stage-specific H3K9me3 occupancy ensures retrotransposon silencing in human pre-implantation embryos.

H3K9me3, as a hallmark of heterochromatin, is important for cell-fate specification. However, it remains unknown how H3K9me3 is reprogrammed during human early embryo development. Here, we profiled genome-wide H3K9me3 in human oocytes and early embryos and discovered stage-specific H3K9me3 deposition on long terminal repeats (LTRs) at the 8-cell and blastocyst stages. We found that 8-cell-specific H3K9me3 was temporarily established in enhancer-like regions, whereas blastocyst-specific H3K9me3 was more stable. DUX and multiple Krüppel-associated box domain zinc finger proteins(KRAB-ZNFs) were identified as potential factors for establishing 8C- and blastocyst-specific H3K9me3, respectively. Intriguingly, our analysis showed that stage-specific H3K9me3 allocation was attenuated by either Dux knockout or Zfp51 knockdown in mouse early embryos. Moreover, we observed the existence of H3K4me3/H3K9me3 and H3K4me3/H3K27me3 bivalent chromatin domains in human blastocysts, priming for lineage differentiation. Together, our data unveil that the epigenetic switch from DNA methylation to H3K9me3 ensures the precise regulation of retrotransposons in human pre-implantation embryos.