GSE130115
Allelic histone-to-DNA methylation switch establishes secondary DMR  to maintain noncanonical imprinting
Faithful maintenance of genomic imprinting is essential for mammalian development.  While germline DNA methylation-dependent (canonical) imprinting is relatively stable during development, the recently discovered oocyte-derived H3K27me3-mediated noncanonical imprinting is mostly transient in early embryos with only a few genes maintain imprinted expression in the extraembryonic lineage.  How these few noncanonical imprinted genes maintain their extraembryonic-specific imprinting is unknown. Here we report that maintenance of extraembryonic-specific noncanonical imprinting requires maternal allele-specific de novo DNA methylation (secondary differentially methylation regions; DMRs) at implantation. The secondary DMRs are located at the gene promoters with paternal allele-specific H3K4me3 preformed during preimplantation development. Importantly, genetic ablation of Eed and DNA methyltransferases revealed that both maternal H3K27me3 and zygotic Dnmt3a/3b are required for establishing secondary DMRs and for maintaining noncanonical imprinting.  Thus, our study not only reveals the mechanism underlying maintenance of noncanonical imprinting, but also sheds light on how histone modifications in oocytes and preimplantation embryos may shape the secondary DMRs in post-implantation embryos. Overall design: Two RNA-seq replicates were performed for Dnmt3l control (CTR) and maternal KO (matKO) morula samples; One replicate of whole genome bisulfite sequencing (WGBS) was performed for Eed CTR and matKO E6.5 extraembryonic ectoderm (ExE); Two and seven RNA-seq replicates were performed for WT and Dnmt3a/3b double KO (DKO) E6.5 ExE; Three RRBS replicates were performed for WT and Dnmt3a/3b DKO E6.5 ExE; Two H3K27me3 CUT&RUN replicates were performed for WT and Dnmt3a/3b DKO E6.5 ExE; Two H3K4me3 CUT&RUN replicates were performed for Eed CTR and matKO morula; One H3K4me3 CUT&RUN replicate was performed for Eed CTR and matKO trophectoderm (TE).