Division of Reproduction and Genetics, First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.
Division of Reproduction and Genetics, First Affiliated Hospital of USTC, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.
Cell Rep. 2022 Mar 22;38(12):110540. doi: 10.1016/j.celrep.2022.110540.
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 of Zfp541 in 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., Prdm9 and Mei1) and their upstream activators (e.g., Meiosin and Rxra), 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.
DSB 机制在减数分裂的细线期和偶线期诱导程序性 DNA 双链断裂 (DSB)，在粗线期开始前被抑制。然而，其生物学意义和潜在机制在很大程度上仍不清楚。在这里，我们报告 ZFP541 对于中期粗线期后 DSB 形成的抑制是必不可少的。在小鼠中删除 Zfp541 会导致 DSB 机制异常募集到染色体轴上，并在晚期粗线期和双线期精母细胞中产生大量 DSB，导致减数分裂停滞在双线期。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 主要结合于早粗线期基因的启动子，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 Meiosin 和 Rxra），并在粗线期精母细胞中维持它们的抑制。我们的结果表明，ZFP541 在粗线期精母细胞中作为转录调节剂发挥作用，协调转录组以确保减数分裂的进行。
