2026-03-02 浙江大学（ZJU）
＜関連情報＞
- https://www.zju.edu.cn/english/2026/0302/c19573a3136508/page.psp
- https://www.science.org/doi/10.1126/science.adv5257
内因性レトロウイルスは異種キメラRNAを合成し、ヒト初期胚の発達を強化する Endogenous retroviruses synthesize heterologous chimeric RNAs to reinforce human early embryo development
Yangquan Xiang, Yuli Qian, Zhengyi Li, Jiaxu Wang, […] , and Hongqing Liang
Science Published:22 Jan 2026
DOI:https://doi.org/10.1126/science.adv5257
Editor’s summary
Zygotic genome activation (ZGA) marks the critical moment when the embryo’s genome is awakened from dormancy. Xiang et al. now show that an ancient viral remnant, the endogenous retrovirus MLT2A1, plays an essential role in human ZGA. MLT2A1 produces chimeric RNAs during ZGA by fusing with various downstream sequences. These chimeras interact with numerous ZGA genes and form an auto-amplifying network promoting widespread, de novo gene activation during ZGA. Reducing MLT2A1 activity halts early human embryo development. Thus, ancient viral sequences have been repurposed to orchestrate the very beginning of human life, a finding that may have relevance for reproductive medicine. —Stella M. Hurtley
Structured Abstract
INTRODUCTION
In human early embryonic development, zygotic genome activation (ZGA) is a pivotal event during which the embryo initiates transcription from its own genome. This process requires a global rewiring of the chromatin landscape and transcription network. ZGA failure often causes developmental arrest, a major contributor to infertility and pregnancy loss. Although investigation into mammalian ZGA models has identified key protein-coding genes essential for ZGA network, the causes of human ZGA failure and early pregnancy loss remain poorly understood, likely reflecting substantial species-specific regulatory differences.
RATIONALE
Retro–transposable elements (retro-TEs) consist of long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and endogenous retroviruses (ERVs). They are highly active during early embryonic development and constitute a substantial proportion of the species-specific transcriptome during ZGA. We hypothesized that retro-TEs could participate in human-specific ZGA regulation. Using ethically approved human in vitro fertilization (IVF) embryos and in vitro reprogrammed eight-cell (8C)–like cells, we investigated the contribution and functional impact of ZGA-specific retro-TEs toward human early embryonic development.
RESULTS
MLT2A1 was specifically up-regulated during ZGA, and its deficiency was associated with developmental arrest in human IVF embryos at the 8C stage. Depleting MLT2A1 RNA in both human embryos and 8C-like cells impaired ZGA gene expression and halted developmental progression. Long-read transcriptome profiling revealed that the majority of MLT2A1 copies generated diverse chimeric transcripts by fusion with downstream sequences, including coding and noncoding sequences, and, most prominently, with other retro-TE subfamilies. Chromatin isolation by RNA purification demonstrated that the variable 3′ fusion regions of these chimeric RNAs increased the sequence complexity of MLT2A1, thereby expanding their genome-targeting potential. On the other hand, RNA pull-down coupled with mass spectrometry showed that the conserved 5′ MLT2A1 region of the chimeric RNAs binds to heterogeneous nuclear ribonucleoprotein U (HNRNPU), recruiting RNA polymerase II (RNAP II) to facilitate transcription. This dual strategy conferred by MLT2A1 chimeric RNAs ensured global induction of a broad spectrum of ZGA genes. Furthermore, by comparing knockdowns of the entire MLT2A1 subfamily versus single copies, we discovered that MLT2A1 subfamily members formed a self-amplifying, positive feedback loop to cross-activate one another. Collectively, these chimeric RNAs orchestrated a robust and decisive transition through ZGA, which is essential for securing early human embryo development.
CONCLUSION
Our study established MLT2A1-derived chimeric RNAs as essential regulators coordinating global transcriptional activation during human ZGA. The distinctive features of MLT2A1 RNAs allowed them to operate as an extensive regulatory network, specifically tailored to drive the widespread de novo transcription that defines ZGA. Furthermore, our findings posited MLT2A1 RNAs as potential surrogate markers for assessing IVF embryo quality and monitoring successful ZGA progression.
MLT2A1 reinforces human ZGA by synthesizing heterologous chimeric RNAs. ZGA-specific MLT2A1 generated chimeric RNAs by fusing with diverse downstream sequences.
Whereas the variable 3′ fusion sequence expanded their genomic DNA targeting capacity, the conserved 5′ MLT2A1 part bound HNRNPU to recruit RNAP II. This mechanism ensured efficient and global ZGA gene induction. Consequently, depleting MLT2A1 RNAs resulted in embryo development arrest. NC, noncoding; Alu, Alu element (a subfamily of SINE); L1, LINE1. [Figure created with BioRender.com]
Abstract
Zygotic genome activation (ZGA) failure leads to developmental arrest and poses a clinical challenge to women’s fertility. We observed that human embryos arresting at the eight-cell ZGA stage exhibited specific down-regulation of endogenous retrovirus MLT2A1. Depleting MLT2A1 resulted in a failure in embryo development and a reduction in ZGA gene expression. Mechanistically, MLT2A1s synthesized chimeric transcripts with downstream coding and noncoding sequences, predominantly with heterologous retro–transposable elements. These diverse fusion sequences expanded the genome-targeting spectrum of MLT2A1 RNAs. Nevertheless, the shared MLT2A1 sequences partnered with heterogeneous nuclear ribonucleoprotein U (HNRNPU) to recruit RNA polymerase II, promoting global transcription of ZGA genes and autoamplification of the MLT2A1 subfamily. Thus, MLT2A1 chimeric RNAs formed an interlocking network that acts synergistically to boost human ZGA and early embryogenesis.
