PDF(Pubmed)
Abstract：
Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.
摘要：
精子具有复杂且对环境敏感的小型非编码RNA（sncRNA）1库，这会影响后代发育和成年表型1-7。附睾中的精子是否直接受到环境线索的影响尚不完全清楚8。在这里，我们使用了两种不同的孕前急性高脂饮食范式来剖析附睾和睾丸对精子sncRNA池和后代健康的贡献。我们显示附睾精子，但不是正在发育的生殖细胞，对环境敏感，并将线粒体tRNA（mt-tRNA）及其片段（mt-tsRNA）鉴定为精子传播因子。在人类中,精子中的mt-tsRNAs与体重指数相关，父亲在怀孕时超重会使后代肥胖风险加倍，并损害代谢健康。涉及线粒体功能的基因突变小鼠的精子sncRNA测序，以及它们野生型后代的代谢表型，提示mt-tsRNAs的上调是线粒体功能障碍的下游。遗传杂交双细胞胚胎的单胚胎转录组学显示了受精时mt-tRNA的精子到卵母细胞的转移，并表明它们参与了早期胚胎转录的控制。我们的研究支持了父亲健康在受孕对后代代谢的重要性，显示mt-tRNAs是饮食诱导的和精子传播的，在生理环境中，受精时精子线粒体RNA的父子代转移。
