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

doi:10.1016/j.isci.2024.109748

Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation

iScience. 2024 Apr 16;27(5):109748. doi: 10.1016/j.isci.2024.109748. eCollection 2024 May 17.

Authors

Chuanbo Sun¹, Ruirui Guo^{2

3}, Xiangyan Ye¹, Shiyi Tang², Manqi Chen², Pei Zhou¹, Miaomiao Yang¹, Caihua Liao¹, Hong Li¹, Bing Lin¹, Congwen Zang¹, Yifei Qi¹, Dingding Han^{1

4}, Yi Sun⁵, Na Li¹, Dengna Zhu⁶, Kaishou Xu⁷, Hao Hu^{1

6}

Affiliations

¹ Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
² Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510275, China.
³ School of Basic Medical Science, Gansu Medical College, Pingliang 744000, Gansu, China.
⁴ Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.
⁵ Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province 510180, China.
⁶ Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁷ Department of Rehabilitation, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510120, China.

Abstract

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 tRNA^phe 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.

Keywords: Developmental biology; Molecular biology; Neuroscience.