2. Academic Validation
  3. Endogenous retroviruses synthesize heterologous chimeric RNAs to reinforce human early embryo development

Endogenous retroviruses synthesize heterologous chimeric RNAs to reinforce human early embryo development

  • Science. 2026 Jan 22;391(6783):eadv5257. doi: 10.1126/science.adv5257.
Yangquan Xiang # 1 2,  Yuli Qian # 1 2,  Zhengyi Li # 1,  Jiaxu Wang # 1 3,  Ruonan Tian 4 5,  Weikang Meng 1,  Jiabao Bu 1,  Fei Huang 6,  Zhipeng Ai 1 2,  Danya Wu 1 2,  Xijia Chen 1,  You Wu 7,  Li Shen 6,  Yun-Shen Chan 8,  Yawei Gao 9,  Jun Ma 10 11,  Wanlu Liu 4 5,  Shaorong Gao 7,  Dan Zhang 1 2,  Hongqing Liang 1 2
Affiliations

Affiliations

  • 1 Institute of Medical Genetics and Development, Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Zhejiang Provincial Birth Defect Control and Prevention Research Center, and Zhejiang International Science and Technology Cooperation Base of Reproductive Health, Hangzhou, China.
  • 3 Stem Cell and Regenerative Biology, Genome Institute of Singapore, A∗STAR, Singapore, Singapore.
  • 4 Department of Rheumatology and Immunology of the Second Affiliated Hospital, and Centre of Biomedical Systems and Informatics of Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Zhejiang Key Laboratory of Medical Imaging Artificial Intelligence, Haining, China.
  • 6 The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 7 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 8 Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, China.
  • 9 State Key Laboratory of Cardiology and Medical Innovation Center, Department of Reproductive Medicine Center, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 10 Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 11 Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, China.
  • # Contributed equally.
PMID: 41570148 DOI: 10.1126/science.adv5257
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.

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