Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation
Chuanbo Sun,
Ruirui Guo,
Xiangyan Ye,
Shiyi Tang,
Manqi Chen,
Pei Zhou,
Miaomiao Yang,
Caihua Liao,
Hong Li,
Bing Lin,
Congwen Zang,
Yifei Qi,
Dingding Han,
Yi Sun,
Na Li,
Dengna Zhu,
Kaishou Xu,
Hao Hu
Affiliations
Chuanbo Sun
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Ruirui Guo
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China; School of Basic Medical Science, Gansu Medical College, Pingliang 744000, Gansu, China
Xiangyan Ye
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Shiyi Tang
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China
Manqi Chen
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China
Pei Zhou
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Miaomiao Yang
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Caihua Liao
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Hong Li
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Bing Lin
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Congwen Zang
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Yifei Qi
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Dingding Han
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Clinical Laboratory, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China
Yi Sun
Department of Neonatology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province 510180, China
Na Li
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
Dengna Zhu
Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Corresponding author
Kaishou Xu
Department of Rehabilitation, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510120, China; Corresponding author
Hao Hu
Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Corresponding author
Summary: We previously reported that loss of function of TYW1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation. However, whether TYW1 loss affects neural differentiation is unknown. In this study, we first demonstrated that TYW1 loss blocked the formation of OHyW in tRNAphe and therefore affected the translation efficiency of UUU codon. Using the brain organoid model, we showed impaired neuron differentiation when TYW1 was depleted. Interestingly, retrotransposons were differentially regulated in TYW1−/− hESCs (human embryonic stem cells). In particular, one kind of human-specific endogenous retrovirus-K (HERVK/HML2), whose reactivation impaired human neurodevelopment, was significantly up-regulated in TYW1−/− hESCs. Consistently, a UUU codon-enriched protein, SMARCAD1, which was a key factor in controlling endogenous retroviruses, was reduced. Taken together, TYW1 loss leads to up-regulation of HERVK in hESCs by down-regulated SMARCAD1, thus impairing neuron differentiation.
