RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis.
RNA binding protein RBM46 regulates mitotic-to-meiotic transition in spermatogenesis.
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RNA结合蛋白RBM46调节精子发生中有丝分裂到减数分裂的转变
DOI：
10.1126/sciadv.abq2945
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发表时间：
2022-08-26
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
精子发生过程中减数分裂的进入需要从有丝分裂到减数分裂基因表达谱的重编程。在减数分裂进入过程中转录调控已被广泛研究，但主转录因子功能的获得不足以下调有丝分裂基因。RNA解旋酶YTHDC2及其伙伴MEIOC是减数分裂进入的重要转录后调控因子。然而，目前尚不清楚是什么控制了YTHDC2/MEIOC的RNA结合特异性。在这里，我们发现RNA结合蛋白RBM46是YTHDC2/MEIOC复合体的一个组成部分。小鼠睾丸特异性Rbm46基因敲除导致不育，有丝分裂向减数分裂转化有缺陷，表型复制全局Ythdc2或Meioc基因敲除。RBM46结合来自YTHDC2富u基序的100个核苷酸内的有丝分裂转录物的3 ' UTR，并靶向这些转录物进行降解。RBM46表达失调与人类男性生育障碍有关。这些发现表明，RBM46/YTHDC2/MEIOC复合物是哺乳动物精子发生过程中下调有丝分裂转录物的主要转录后调控因子，这对理解减数分裂相关的生育障碍具有重要意义。RBM46/YTHDC2/MEIOC复合体是调控有丝分裂向减数分裂转变的主要转录后调控因子。
Meiosis entry during spermatogenesis requires reprogramming from mitotic to meiotic gene expression profiles. Transcriptional regulation has been extensively studied in meiosis entry, but gain of function for master transcription factors is insufficient to down-regulate mitotic genes. RNA helicase YTHDC2 and its partner MEIOC emerge as essential posttranscriptional regulators of meiotic entry. However, it is unclear what governs the RNA binding specificity of YTHDC2/MEIOC. Here, we identified RNA binding protein RBM46 as a component of the YTHDC2/MEIOC complex. Testis-specific Rbm46 knockout in mice causes infertility with defective mitotic-to-meiotic transition, phenocopying global Ythdc2 or Meioc knockout. RBM46 binds to 3′ UTR of mitotic transcripts within 100 nucleotides from YTHDC2 U-rich motifs and targets these transcripts for degradation. Dysregulated RBM46 expression is associated with human male fertility disorders. These findings establish the RBM46/YTHDC2/MEIOC complex as the major posttranscriptional regulator responsible for down-regulating mitotic transcripts during meiosis entry in mammalian spermatogenesis, with implications for understanding meiosis-related fertility disorders. The RBM46/YTHDC2/MEIOC complex is the major posttranscriptional regulator that regulates the mitosis-to-meiosis transition.
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