NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit
Abstract Transcription elongation, especially RNA polymerase II (Pol II) pause-release, is less studied than transcription initiation in regulating gene expression during meiosis. It is also unclear how transcription elongation interplays with transcription initiation. Here, we show that depletion o...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55579-y |
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| author | Zhenlong Kang Chen Xu Shuai Lu Jie Gong Ruoyu Yan Gan Luo Yuanyuan Wang Qing He Yifei Wu Yitong Yan Baomei Qian Shenglin Han Zhiwen Bu Jinwen Zhang Xian Xia Liang Chen Zhibin Hu Mingyan Lin Zheng Sun Yayun Gu Lan Ye |
| author_facet | Zhenlong Kang Chen Xu Shuai Lu Jie Gong Ruoyu Yan Gan Luo Yuanyuan Wang Qing He Yifei Wu Yitong Yan Baomei Qian Shenglin Han Zhiwen Bu Jinwen Zhang Xian Xia Liang Chen Zhibin Hu Mingyan Lin Zheng Sun Yayun Gu Lan Ye |
| author_sort | Zhenlong Kang |
| collection | DOAJ |
| description | Abstract Transcription elongation, especially RNA polymerase II (Pol II) pause-release, is less studied than transcription initiation in regulating gene expression during meiosis. It is also unclear how transcription elongation interplays with transcription initiation. Here, we show that depletion of NKAPL, a testis-specific protein distantly related to RNA splicing factors, causes male infertility in mice by blocking the meiotic exit and downregulating haploid genes. NKAPL binds to promoter-associated nascent transcripts and co-localizes with DNA-RNA hybrid R-loop structures at GAA-rich loci to enhance R-loop formation and facilitate Pol II pause-release. NKAPL depletion prolongs Pol II pauses and stalls the SOX30/HDAC3 transcription initiation complex on the chromatin. Genetic variants in NKAPL are associated with azoospermia in humans, while mice carrying an NKAPL frameshift mutation (M349fs) show defective meiotic exit and transcriptomic changes similar to NKAPL depletion. These findings identify NKAPL as an R-loop-recognizing factor that regulates transcription elongation, which coordinates the meiotic-to-postmeiotic transcriptome switch in alliance with the SOX30/HDAC3-mediated transcription initiation. |
| format | Article |
| id | doaj-art-408225945be047a98f5a478f2ce4b420 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-408225945be047a98f5a478f2ce4b4202025-01-19T12:29:57ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-024-55579-yNKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exitZhenlong Kang0Chen Xu1Shuai Lu2Jie Gong3Ruoyu Yan4Gan Luo5Yuanyuan Wang6Qing He7Yifei Wu8Yitong Yan9Baomei Qian10Shenglin Han11Zhiwen Bu12Jinwen Zhang13Xian Xia14Liang Chen15Zhibin Hu16Mingyan Lin17Zheng Sun18Yayun Gu19Lan Ye20State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityDepartment of Neurobiology, School of Basic Medical Science, Nanjing Medical UniversityReproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityJiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical UniversityRNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityDepartment of Neurobiology, School of Basic Medical Science, Nanjing Medical UniversityDepartment of Medicine, Baylor College of MedicineState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical UniversityAbstract Transcription elongation, especially RNA polymerase II (Pol II) pause-release, is less studied than transcription initiation in regulating gene expression during meiosis. It is also unclear how transcription elongation interplays with transcription initiation. Here, we show that depletion of NKAPL, a testis-specific protein distantly related to RNA splicing factors, causes male infertility in mice by blocking the meiotic exit and downregulating haploid genes. NKAPL binds to promoter-associated nascent transcripts and co-localizes with DNA-RNA hybrid R-loop structures at GAA-rich loci to enhance R-loop formation and facilitate Pol II pause-release. NKAPL depletion prolongs Pol II pauses and stalls the SOX30/HDAC3 transcription initiation complex on the chromatin. Genetic variants in NKAPL are associated with azoospermia in humans, while mice carrying an NKAPL frameshift mutation (M349fs) show defective meiotic exit and transcriptomic changes similar to NKAPL depletion. These findings identify NKAPL as an R-loop-recognizing factor that regulates transcription elongation, which coordinates the meiotic-to-postmeiotic transcriptome switch in alliance with the SOX30/HDAC3-mediated transcription initiation.https://doi.org/10.1038/s41467-024-55579-y |
| spellingShingle | Zhenlong Kang Chen Xu Shuai Lu Jie Gong Ruoyu Yan Gan Luo Yuanyuan Wang Qing He Yifei Wu Yitong Yan Baomei Qian Shenglin Han Zhiwen Bu Jinwen Zhang Xian Xia Liang Chen Zhibin Hu Mingyan Lin Zheng Sun Yayun Gu Lan Ye NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit Nature Communications |
| title | NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit |
| title_full | NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit |
| title_fullStr | NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit |
| title_full_unstemmed | NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit |
| title_short | NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit |
| title_sort | nkapl facilitates transcription pause release and bridges elongation to initiation during meiosis exit |
| url | https://doi.org/10.1038/s41467-024-55579-y |
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