Montgomery Ty, Uh Kyungjun, Lee Kiho
Division of Animal Sciences, University of Missouri, Columbia, MO, United States.
Futuristic Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si, Republic of Korea.
Front Cell Dev Biol. 2024 Aug 1;12:1358649. doi: 10.3389/fcell.2024.1358649. eCollection 2024.
Mammalian embryo development is initiated by the union of paternal and maternal gametes. Upon fertilization, their epigenome landscape is transformed through a series of finely orchestrated mechanisms that are crucial for survival and successful embryogenesis. Specifically, maternal or oocyte-specific reprogramming factors modulate germ cell specific epigenetic marks into their embryonic states. Rapid and dynamic changes in epigenetic marks such as DNA methylation and histone modifications are observed during early embryo development. These changes govern the structure of embryonic genome prior to zygotic genome activation. Differential changes in epigenetic marks are observed between paternal and maternal genomes because the structure of the parental genomes allows interaction with specific oocyte reprogramming factors. For instance, the paternal genome is targeted by the TET family of enzymes which oxidize the 5-methylcytosine (5mC) epigenetic mark into 5-hydroxymethylcytosine (5hmC) to lower the level of DNA methylation. The maternal genome is mainly protected from TET3-mediated oxidation by the maternal factor, STELLA. The TET3-mediated DNA demethylation occurs at the global level and is clearly observed in many mammalian species. Other epigenetic modulating enzymes, such as DNA methyltransferases, provide fine tuning of the DNA methylation level by initiating methylation. The mechanisms which initiate the epigenetic reprogramming of gametes are critical for proper activation of embryonic genome and subsequent establishment of pluripotency and normal development. Clinical cases or diseases linked to mutations in reprogramming modulators exist, emphasizing the need to understand mechanistic actions of these modulators. In addition, embryos generated via embryo production system often present epigenetic abnormalities. Understanding mechanistic actions of the epigenetic modulators will potentially improve the well-being of individuals suffering from these epigenetic disorders and correct epigenetic abnormalities in embryos produced . This review will summarize the current understanding of epigenetic reprogramming by TET enzymes during early embryogenesis and highlight its clinical relevance and potential implication for assisted reproductive technologies.
哺乳动物胚胎发育始于父本和母本配子的结合。受精后，它们的表观基因组景观通过一系列精心编排的机制发生转变，这些机制对生存和成功的胚胎发生至关重要。具体而言，母源或卵母细胞特异性重编程因子将生殖细胞特异性表观遗传标记调节为胚胎状态。在早期胚胎发育过程中，观察到表观遗传标记如DNA甲基化和组蛋白修饰的快速动态变化。这些变化在合子基因组激活之前决定了胚胎基因组的结构。父本和母本基因组之间观察到表观遗传标记的差异变化，因为亲本基因组的结构允许与特定的卵母细胞重编程因子相互作用。例如，父本基因组被TET酶家族靶向，该家族将5-甲基胞嘧啶（5mC）表观遗传标记氧化为5-羟甲基胞嘧啶（5hmC）以降低DNA甲基化水平。母本基因组主要通过母源因子STELLA免受TET3介导的氧化。TET3介导的DNA去甲基化在整体水平上发生，并且在许多哺乳动物物种中都能清楚地观察到。其他表观遗传调节酶，如DNA甲基转移酶，通过启动甲基化来微调DNA甲基化水平。启动配子表观遗传重编程的机制对于胚胎基因组的正确激活以及随后多能性的建立和正常发育至关重要。存在与重编程调节因子突变相关的临床病例或疾病，这强调了理解这些调节因子的作用机制的必要性。此外，通过胚胎生产系统产生的胚胎常常存在表观遗传异常。了解表观遗传调节因子的作用机制可能会改善患有这些表观遗传疾病的个体的健康状况，并纠正所产生胚胎中的表观遗传异常。本综述将总结目前对早期胚胎发生过程中TET酶表观遗传重编程的理解，并强调其临床相关性以及对辅助生殖技术的潜在影响。
