Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
Laboratory for Epigenome Inheritance, Riken Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.
BMC Genomics. 2024 Apr 5;25(1):344. doi: 10.1186/s12864-024-10192-7.
Genome-wide DNA demethylation occurs in mammalian primordial germ cells (PGCs) as part of the epigenetic reprogramming important for gametogenesis and resetting the epigenetic information for totipotency. Dppa3 (also known as Stella or Pgc7) is highly expressed in mouse PGCs and oocytes and encodes a factor essential for female fertility. It prevents excessive DNA methylation in oocytes and ensures proper gene expression in preimplantation embryos: however, its role in PGCs is largely unexplored. In the present study, we investigated whether or not DPPA3 has an impact on CG methylation/demethylation in mouse PGCs.
We show that DPPA3 plays a role in genome-wide demethylation in PGCs even before sex differentiation. Dppa3 knockout female PGCs show aberrant hypermethylation, most predominantly at H3K9me3-marked retrotransposons, which persists up to the fully-grown oocyte stage. DPPA3 works downstream of PRDM14, a master regulator of epigenetic reprogramming in embryonic stem cells and PGCs, and independently of TET1, an enzyme that hydroxylates 5-methylcytosine.
The results suggest that DPPA3 facilitates DNA demethylation through a replication-coupled passive mechanism in PGCs. Our study identifies DPPA3 as a novel epigenetic reprogramming factor in mouse PGCs.
基因组范围的 DNA 去甲基化发生在哺乳动物原始生殖细胞（PGCs）中，是生殖发生和重置全能性的表观遗传重编程的重要组成部分。Dppa3（也称为 Stella 或 Pgc7）在小鼠 PGCs 和卵母细胞中高度表达，编码对雌性生育力至关重要的因子。它可防止卵母细胞中过多的 DNA 甲基化，并确保植入前胚胎中的适当基因表达：然而，其在 PGCs 中的作用在很大程度上尚未被探索。在本研究中，我们研究了 DPPA3 是否会影响小鼠 PGCs 中的 CG 甲基化/去甲基化。
我们表明，DPPA3 在性别分化之前的 PGCs 中发挥作用，甚至在全基因组去甲基化中发挥作用。Dppa3 敲除雌性 PGCs 显示出异常的过度甲基化，主要是在 H3K9me3 标记的逆转录转座子上，这种现象一直持续到完全成熟的卵母细胞阶段。DPPA3 作用于 PRDM14 下游，PRDM14 是胚胎干细胞和 PGCs 中表观遗传重编程的主要调节因子，并且独立于 TET1，后者是一种将 5-甲基胞嘧啶羟化的酶。
这些结果表明，DPPA3 通过 PGCs 中的复制偶联被动机制促进 DNA 去甲基化。我们的研究鉴定了 DPPA3 作为小鼠 PGCs 中一种新的表观遗传重编程因子。
