Developmental genome-wide DNA methylation asymmetry between mouse placenta and embryo

In early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri–implantation stages, the <i>de novo</i> methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal <i>de novo</i> methyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.

早期胚胎中，DNA甲基化（DNA methylation）会经历重塑以启动发育程序，但目前学界对胚胎细胞与胎盘细胞间甲基化标记获取不均的具体机制仍不甚明晰。为深入解析该现象，本研究构建了小鼠妊娠中期（胚胎发育第10.5天，E10.5）胚胎与胎盘的高分辨率DNA甲基化图谱。本研究揭示了一类特定的差异甲基化区域（differentially methylated regions, DMRs）亚型，这类区域直接介导了妊娠中期胚胎与胎盘DNA甲基化模式间的发育不对称性。研究表明，这种不对称性在植入后孕体（E3.5-E6.5）的甲基化标记获取阶段快速形成，且此类甲基化模式在整个产前发育阶段及体细胞组织中，于各类差异甲基化区域亚型间均保持持久稳定。本研究还发现，在着床阶段，DNMT3B的从头（de novo）甲基转移酶活性是不对称差异甲基化区域上甲基化标记形成的主要驱动因素；且在上胚层与胚外外胚层中，DNMT3B可在很大程度上补偿DNMT3A的缺失，而DNMT3A在DNMT3B缺失时仅能发挥部分补偿作用。但随着发育进程推进，当DNMT3A成为主要的从头甲基转移酶时，DNMT3B对差异甲基化区域的补偿性DNA甲基化机制的作用效果逐渐减弱。