UHRF1-repressed 5 '-hydroxymethylcytosine is essential for the male meiotic prophase I
UHRF1-repressed 5 '-hydroxymethylcytosine is essential for the male meiotic prophase I
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DOI：
10.1038/s41419-020-2333-3
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发表时间：
2020
影响因子：
9
通讯作者：
Li Runsheng
中科院分区：
文献类型：
--
作者：
Pan Hongjie;Jiang Ning;Sun Shenfei;Jiang Hanwei;Xu Jianze;Jiang Xiaohua;Gao Qian;Li Liang;Wu Haili;Zheng Huajun;Qi Qi;Li Tianqi;Zhang Meixing;Zhang Lingling;Wan Xiaofeng;Lin Xinhua;Wong Jiemin;Shi Qinghua;Li Runsheng
5 ′-羟甲基胞嘧啶（5 hmC）是一种重要的5 ′-胞嘧啶修饰，在雄性减数分裂前期发生高度有序的改变。然而，这一动态变化的调控机制以及5 hmC在减数分裂中的功能仍不清楚。使用基因敲除小鼠模型，我们表明，UHRF 1调节男性减数分裂。UHRF 1缺乏导致减数分裂失败和雄性不育。在机制上，Uhrf 1基因敲除可显著改变精母细胞减数分裂基因的表达谱，导致5 hmC水平的整体升高。在转录起始位点（TSS）的hyper-5 hmC的富集与基因下调高度相关。此外，TET 1酶水平升高可能导致Uhrf 1基因敲除精母细胞中5 hmC水平升高。最后，我们证实了Uhrf 1，一个在雄性减数分裂中起关键作用的基因，通过下调TET 1来抑制hyper-5 hmC。此外，UHRF 1促进RNA聚合酶II（RNA-pol 2）加载，以促进基因转录。因此，我们的研究表明，5 hmC的动态变化的一个潜在的调节机制，并参与了雄性减数分裂的表观遗传调控。
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.Uhrf1knockout 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 theUhrf1knockout spermatocytes. Finally, we reportedUhrf1, 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.