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<p>Long non-coding RNAs (lncRNAs) play crucial roles in diverse mammalian physiological processes, yet their functions in spermatogenesis remain largely underexplored. Here, we identify a unique class of conserved haploid spermatid-associated lncRNAs (cHS-LncRNAs) defined by sequence conservation, testis-restricted expression, and elevated levels in haploid spermatids. Among these, testis-specific conserved lncRNA 1 (<i>Tscl1</i>) is the most highly expressed in round spermatids. <i>Tscl1</i>-null male mice exhibit reduced sperm motility, disorganized mitochondrial sheaths, abnormal fatty acid metabolism, and complete infertility. Mechanistically, <i>Tscl1</i> directly binds PIWIL1 and HuR via its 5′ stem-loop and multiple AU-rich elements, respectively. This interaction promotes assembly of a PIWIL1/eIF3f/HuR/eIF4G3 complex that enhances translation of fatty-acid-metabolism-related mRNAs within the chromatoid body. Notably, <i>TSCL1</i> variants disrupting the PIWIL1-binding region are significantly enriched in patients with non-obstructive azoospermia (NOA) compared to fertile controls. Collectively, our findings uncover a critical role for <i>Tscl1</i> in modulating translation during spermiogenesis and implicate <i>TSCL1</i> as a potential pathogenic locus in human male infertility.</p>

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Male specific conserved LncRNA TSCL1 regulated target mRNA translation by interaction with PIWIL1

  • 期刊论文

  • 发表日期：

    2025年9月20日

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  • Shuai Lu,
  • Yang Li,
  • Chenmeijie Li,
  • Zhongyu Zou,
  • Xiaoxi Xu,
  • Shijie Zhu,
  • Beibei Yang,
  • Gaoming Tang,
  • Haoran Chen,
  • Yuchen Wang,
  • Feng Li,
  • Na Qin,
  • Cheng Wang,
  • Hongbing Shen,
  • Zhibin Hu,
  • Yayun Gu

摘要

Long non-coding RNAs (lncRNAs) play crucial roles in diverse mammalian physiological processes, yet their functions in spermatogenesis remain largely underexplored. Here, we identify a unique class of conserved haploid spermatid-associated lncRNAs (cHS-LncRNAs) defined by sequence conservation, testis-restricted expression, and elevated levels in haploid spermatids. Among these, testis-specific conserved lncRNA 1 (Tscl1) is the most highly expressed in round spermatids. Tscl1-null male mice exhibit reduced sperm motility, disorganized mitochondrial sheaths, abnormal fatty acid metabolism, and complete infertility. Mechanistically, Tscl1 directly binds PIWIL1 and HuR via its 5′ stem-loop and multiple AU-rich elements, respectively. This interaction promotes assembly of a PIWIL1/eIF3f/HuR/eIF4G3 complex that enhances translation of fatty-acid-metabolism-related mRNAs within the chromatoid body. Notably, TSCL1 variants disrupting the PIWIL1-binding region are significantly enriched in patients with non-obstructive azoospermia (NOA) compared to fertile controls. Collectively, our findings uncover a critical role for Tscl1 in modulating translation during spermiogenesis and implicate TSCL1 as a potential pathogenic locus in human male infertility.