Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Mus musculus

Increasing evidences indicate diet-induced metabolic disorder could be paternally inherited, but the exact sperm epigenetic carrier remains unclear. Here, in a paternal high-fat diet (HFD) mouse model, we revealed that a highly enriched subset of sperm small RNAs (30-34 nt) that derived from the 5’ halves of tRNAs (tsRNAs), exhibit changes in both expression profiles and RNA modifications. Injection of sperm tsRNAs from HFD male but not synthetic tsRNAs lacking RNA modifications, into normal zygotes generated metabolic disorders in the F1 offspring. Injection of HFD sperm tsRNAs derails gene expression in both early embryos and islets of F1 offspring, enriched in metabolic pathways, but unrelated to DNA methylation at CpG-enriched region. Collectively, we uncover sperm tsRNAs as a type of “epigenetic carrier” that mediate intergenerational inheritance of acquired traits. Overall design: Mature sperm small-RNA profiles between High-fat-diet (HFD) and Normal-diet (ND) males; Transcriptional profiles of 8-cell embryos and balstocysts that developed from zygotes that injected with sperm RNAs from HFD vs ND males. Transcriptional profiles and RRBS profiles of islets of F1 offsrping that generated from zygotes that injected with sperm RNAs from HFD vs ND males.

越来越多的研究证据表明，饮食诱导的代谢紊乱可经父系遗传，但其确切的精子表观遗传载体仍未明确。本研究在父系高脂饮食（High-fat diet, HFD）小鼠模型中发现，一类高度富集的精子小RNA（30~34 nt）——源自转运RNA（transfer RNA, tRNA）的5'端片段（tsRNAs）——其表达谱与RNA修饰状态均发生显著改变。将HFD雄鼠的精子tsRNAs而非缺乏RNA修饰的人工合成tsRNAs注射至正常受精卵中，可使F1子代出现代谢紊乱表型。向受精卵注射HFD雄鼠的精子tsRNAs，会干扰F1子代早期胚胎与胰岛的基因表达，此类差异表达基因显著富集于代谢通路，但与CpG富集区域的DNA甲基化水平无关。综上，本研究揭示精子tsRNAs是一类介导获得性状代间遗传的“表观遗传载体”。整体实验设计：对比高脂饮食（HFD）与正常饮食（Normal diet, ND）雄鼠的成熟精子小RNA表达谱；分析注射HFD与ND雄鼠精子RNA的受精卵发育而来的8细胞胚胎与囊胚的转录组谱；分析注射HFD与ND雄鼠精子RNA的受精卵发育而来的F1子代胰岛的转录组谱与简化代表性亚硫酸氢盐测序（Reduced Representation Bisulfite Sequencing, RRBS）谱。