ZFP541 maintains the repression of pre-pachytene transcriptional programs and promotes male meiosis progression
ZFP541 maintains the repression of pre-pachytene transcriptional programs and promotes male meiosis progression
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ZFP541维持对粗线期前转录程序的抑制并促进雄性减数分裂进程
DOI：
10.1016/j.celrep.2022.110540
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发表时间：
2022
期刊：
影响因子：
8.8
通讯作者：
Qinghua Shi
中科院分区：
文献类型：
--
作者：
Jianze Xu;Jianing Gao;Junyan Liu;Xue Huang;Huan Zhang;Ao Ma;Jingwei Ye;Xingxia Zhang;Yang Li;Gang Yang;Hao Yin;Ranjha Khan;Tao Li;Suixing Fan;Xiaohua Jiang;Yuanwei Zhang;Hanwei Jiang;Hui Ma;Qinghua Shi
减数分裂过程中，在瘦素期和zygotene期诱导程序性DNA双链断裂（DSB）的DSB机制在粗线期开始前被抑制。然而，其生物学意义和潜在机制仍不清楚。在这里，我们报道了ZFP541对于抑制中厚线期后DSB的形成是必不可少的。在小鼠中，zfp541的缺失导致DSB机制在染色体轴上的异常募集，并在粗线期和二倍子期精子细胞中产生大量DSB，导致二倍子期减数分裂停止。单细胞RNA测序（scRNA-seq）和染色质免疫沉淀（ChIP）测序数据的综合分析表明，ZFP541主要结合粗线素前基因启动子，包括减数分裂DSB形成相关基因（如prdm9和mei1）及其上游激活子（如MeiosinandRxra），并在粗线素精母细胞中维持其抑制。我们的研究结果表明，ZFP541在粗线精母细胞中作为转录调节因子，协调转录组以确保减数分裂的进展。
The DSB machinery, which induces the programmed DNA double-strand breaks (DSBs) in the leptotene and zygotene stages during meiosis, is suppressed before the onset of the pachytene stage. However, the biological significance and underlying mechanisms remain largely unclear. Here, we report that ZFP541 is indispensable for the suppression of DSB formation after mid-pachytene. The deletion ofZfp541in mice causes the aberrant recruitment of DSB machinery to chromosome axes and generation of massive DSBs in late pachytene and diplotene spermatocytes, leading to meiotic arrest at the diplotene stage. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data indicate that ZFP541 predominantly binds to promoters of pre-pachytene genes, including meiotic DSB formation-related genes (e.g.,Prdm9andMei1) and their upstream activators (e.g.,MeiosinandRxra), and maintains their repression in pachytene spermatocytes. Our results reveal that ZFP541 functions as a transcriptional regulator in pachytene spermatocytes, orchestrating the transcriptome to ensure meiosis progression.