Mechanisms regulating meiotic progression in mammals are poorly understood. The N⁶-methyladenosine (m⁶A) reader and 3′ → 5′ RNA helicase YTHDC2 switches cells from mitotic to meiotic gene expression programs and is essential for meiotic entry, but how this critical cell fate change is accomplished is unknown. Here, we provide insight into its mechanism and implicate YTHDC2 in having a broad role in gene regulation during multiple meiotic stages. Unexpectedly, mutation of the m⁶A-binding pocket of YTHDC2 had no detectable effect on gametogenesis and mouse fertility, suggesting that YTHDC2 function is m⁶A-independent. Supporting this conclusion, CLIP data defined YTHDC2-binding sites on mRNA as U-rich and UG-rich motif-containing regions within 3′ UTRs and coding sequences, distinct from the sites that contain m⁶A during spermatogenesis. Complete loss of YTHDC2 during meiotic entry did not substantially alter translation of its mRNA binding targets in whole-testis ribosome profiling assays but did modestly affect their steady-state levels. Mutation of the ATPase motif in the helicase domain of YTHDC2 did not affect meiotic entry, but it blocked meiotic prophase I progression, causing sterility. Our findings inform a model in which YTHDC2 binds transcripts independent of m⁶A status and regulates gene expression during multiple stages of meiosis by distinct mechanisms.

中文翻译：

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YTHDC2 控制配子发生需要解旋酶活性而不是 m6A 结合

调节哺乳动物减数分裂进程的机制知之甚少。N ⁶ -甲基腺苷 (m ⁶ A) 读取器和 3' → 5' RNA 解旋酶 YTHDC2 将细胞从有丝分裂切换到减数分裂基因表达程序，并且对于进入减数分裂至关重要，但这种关键的细胞命运变化是如何实现的尚不清楚。在这里，我们提供了对其机制的深入了解，并暗示 YTHDC2 在多个减数分裂阶段的基因调控中具有广泛的作用。出乎意料的是，YTHDC2 的 m ⁶ A 结合袋的突变对配子发生和小鼠生育能力没有可检测的影响，表明 YTHDC2 的功能是 m ⁶A-独立的。支持这一结论的是，CLIP 数据将 mRNA 上的 YTHDC2 结合位点定义为 3' UTR 和编码序列中富含 U 和 UG 的基序区域，与精子发生过程中含有 m 6 A 的位点^不同。在减数分裂进入过程中 YTHDC2 的完全丢失并没有显着改变其在全睾丸核糖体分析中的 mRNA 结合靶标的翻译，但适度影响了它们的稳态水平。YTHDC2 解旋酶域中 ATPase 基序的突变不影响减数分裂进入，但它阻止了减数分裂前期 I 进程，导致不育。我们的研究结果提供了一个模型，其中 YTHDC2 结合独立于 m ⁶ A 状态的转录物，并通过不同的机制在减数分裂的多个阶段调节基因表达。