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Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation

ABSTRACT: Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation

PROVIDER: PRJNA1091942 | ENA |

REPOSITORIES: ENA

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Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation

Project description: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 affect neural differentiation is unknown. In this study, we first demonstrated that TYW1 loss blocked the formation of OHyW in tRNAphe, 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. 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 upregulation of HERVK in hESCs by down-regulated SMARCAD1, thus impairing neuron differentiation.

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