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5mC and 5hmC dynamics during PGC reprogramming and role of Tet1 in female meiosis

机译：PGC重编程过程中的5mC和5hmC动态以及Tet1在女性减数分裂中的作用

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Meiosis is a germ-cell-specific cell division processthrough which haploid gametes are produced for sexualreproduction. Before the initiation of meiosis, mouse primordialgerm cells undergo a series of epigenetic reprogrammingsteps, including the global erasure of DNAmethylation at the 5-position of cytosine (5mC) in CpGrichDNA. However, the 5mC dynamics and its relationshipwith the generation of 5-hydroxymethylcytosine(5hmC) during the reprogramming process are not clear.Here we analyzed the dynamics of 5mC and 5hmC duringPGC reprograming. Unexpectedly, we found a “blankperiod” (E8.5-9.5) in which both 5mC and 5hmC are low.After that, 5hmC level increases and reaches its peak atE10.5 and gradually decreases until E13.5. Interestingly,5hmC is enriched in chromocenter during this period ina Tet1 -dependent manner. While this germ cell-specific5hmC subnuclear localization pattern is maintained infemale germ cells till mature oocytes, such pattern is graduallylost in male germ cells as mitosis resumes at neonatalstage. Using a loss-of-function approach in mice,we show that Tet1 has an important role in regulatingmeiosis in mouse oocytes. Tet1 deficiency significantlyreduces female germ-cell numbers and fertility. Univalentchromosomes and unresolved DNA double-strand breaksare also observed in Tet1-deficient oocytes. Tet1 deficiencydoes not greatly affect the genome-wide demethylation,but leads to defective DNA demethylation anddecreased expression of a subset of meiotic genes. Ourstudy thus not only reveals the dynamics of 5mC and5hmC during PGC reprogramming, but also demonstratea function for Tet1 in meiosis and meiotic gene activationin female germ cells.
机译：减数分裂是生殖细胞特异的细胞分裂过程，通过该过程产生单倍体配子用于有性生殖。在减数分裂开始之前，小鼠原初胚细胞经历了一系列表观遗传重编程步骤，包括在CpGrichDNA胞嘧啶（5mC）的5位全局清除DNA甲基化。然而，目前尚不清楚5mC动力学及其与5-羟甲基胞嘧啶（5hmC）的重编程过程之间的关系。在这里，我们分析了PGC重编程期间5mC和5hmC的动力学。出乎意料的是，我们发现了一个“空白期”（E8.5-9.5），其中5mC和5hmC都较低。此后，5hmC的水平升高并在E10.5达到峰值，然后逐渐降低直到E13.5。有趣的是，在此期间5hmC以Tet1依赖性方式富集了色心。尽管这种生殖细胞特异性的5hmC亚核定位模式在雌性生殖细胞中一直保持到成熟的卵母细胞，但随着有丝分裂在新生阶段恢复，这种模式在雄性生殖细胞中逐渐消失。在小鼠中使用功能丧失方法，我们表明Tet1在调节小鼠卵母细胞的减数分裂中具有重要作用。 Tet1缺乏症会明显减少女性生殖细胞数量和生育能力。在缺乏Tet1的卵母细胞中也观察到单价染色体和未解析的DNA双链断裂。 Tet1缺陷并不会在很大程度上影响全基因组的去甲基化，但会导致缺陷的DNA脱甲基和减数分裂基因子集的表达下降。因此，我们的研究不仅揭示了PGC重编程过程中5mC和5hmC的动态，而且还证明了Tet1在女性生殖细胞的减数分裂和减数分裂基因激活中的功能。

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