A hominoid-specific endogenous retrovirus has rewired the gene regulatory network shared between primordial germ cells and naïve pluripotent cells

Although the gene regulatory networks of germ cells are critical for gamete integrity, these networks have been diversified during mammalian evolution. Here, we show that numerous copies of LTR5_Hs, a hominoid-specific endogenous retrovirus (ERV), function as enhancers in both human primordial germ cells (PGCs) and naïve pluripotent cells. Multiomics analysis suggested that PGCs and naïve pluripotent cells exhibit a similar transcriptome signature, and enhancers derived from LTR5_Hs contribute to establishing such similarity. LTR5_Hs appears to be activated by transcription factors critical in both cell types (KLF4, TFAP2C, NANOG, and CBFA2T2). Comparative transcriptome analysis between humans and macaques suggested that the expression of many genes in PGCs and naïve pluripotent cells has been upregulated by LTR5_Hs insertions in the hominoid lineage. Together, this study suggests that LTR5_Hs insertions have rewired and finetuned the gene regulatory network shared between PGCs and naïve pluripotent cells during hominoid evolution.

尽管生殖细胞的基因调控网络对配子完整性至关重要，但这类网络在哺乳动物演化过程中已发生分化。本研究发现，作为类人猿特异性内源逆转录病毒（endogenous retrovirus, ERV）的LTR5_Hs，其多个拷贝在人类原始生殖细胞（primordial germ cells, PGCs）与初始态多能细胞（naïve pluripotent cells）中均发挥增强子功能。多组学分析显示，原始生殖细胞与初始态多能细胞具有相似的转录组特征，而源自LTR5_Hs的增强子有助于建立这种相似性。LTR5_Hs的激活似乎依赖于两类细胞中均关键的转录因子（KLF4、TFAP2C、NANOG及CBFA2T2）。人类与猕猴的比较转录组分析表明，在类人猿谱系中，LTR5_Hs的插入事件上调了大量原始生殖细胞及初始态多能细胞内的基因表达。综上，本研究表明，在类人猿演化过程中，LTR5_Hs的插入事件重新连接并精细调控了原始生殖细胞与初始态多能细胞共有的基因调控网络。