National Health Commission (NHC) Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, 200032, Shanghai, P.R. China.
State Key Laboratory of Genetic Engineering, Institute of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, 200438, Shanghai, P.R. China.
Cell Death Dis. 2020 Feb 21;11(2):142. doi: 10.1038/s41419-020-2333-3.
5'-hydroxymethylcytosine (5hmC), an important 5'-cytosine modification, is altered highly in order in male meiotic prophase. However, the regulatory mechanism of this dynamic change and the function of 5hmC in meiosis remain largely unknown. Using a knockout mouse model, we showed that UHRF1 regulated male meiosis. UHRF1 deficiency led to failure of meiosis and male infertility. Mechanistically, the deficiency of UHRF1 altered significantly the meiotic gene profile of spermatocytes. Uhrf1 knockout induced an increase of the global 5hmC level. The enrichment of hyper-5hmC at transcriptional start sites (TSSs) was highly associated with gene downregulation. In addition, the elevated level of the TET1 enzyme might have contributed to the higher 5hmC level in the Uhrf1 knockout spermatocytes. Finally, we reported Uhrf1, a key gene in male meiosis, repressed hyper-5hmC by downregulating TET1. Furthermore, UHRF1 facilitated RNA polymerase II (RNA-pol2) loading to promote gene transcription. Thus our study demonstrated a potential regulatory mechanism of 5hmC dynamic change and its involvement in epigenetic regulation in male meiosis.
5'-羟甲基胞嘧啶（5hmC）是一种重要的 5'-胞嘧啶修饰物，在雄性减数分裂前期高度有序地改变。然而，这种动态变化的调控机制以及 5hmC 在减数分裂中的功能在很大程度上仍然未知。我们使用一种敲除小鼠模型表明，UHRF1 调控雄性减数分裂。UHRF1 缺乏导致减数分裂失败和雄性不育。在机制上，UHRF1 的缺乏显著改变了精母细胞的减数分裂基因谱。Uhrf1 敲除导致全局 5hmC 水平升高。转录起始位点（TSS）处的超 5hmC 富集与基因下调高度相关。此外，TET1 酶的升高水平可能导致 Uhrf1 敲除精母细胞中更高的 5hmC 水平。最后，我们报告了 Uhrf1，一种减数分裂中关键的雄性基因，通过下调 TET1 来抑制超 5hmC。此外，UHRF1 促进 RNA 聚合酶 II（RNA-pol2）加载以促进基因转录。因此，我们的研究表明了 5hmC 动态变化及其在雄性减数分裂中的表观遗传调控中的潜在调控机制。
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