Induction of fetal hemoglobin to overcome adult β-globin gene deficiency is an effective therapeutic strategy to ameliorate human β-hemoglobinopathies. Previous work has revealed that fetal γ-globin can be translationally induced via integrated stress signaling, but other studies have indicated that activating stress may eventually suppress γ-globin expression transcriptionally. The mechanism by which γ-globin expression is regulated at the translational level remains largely unknown, limiting our ability to determine whether activating stress is a realistic therapeutic option for these disorders. In this study, we performed a functional CRISPR screen targeting protein arginine methyltransferases (PRMTs) to look for changes in γ-globin expression in K562 cells. We not only discovered that several specific PRMTs may block γ-globin transcription, but also revealed PRMT1 as a unique family member that is able to suppress γ-globin synthesis specifically at the translational level. We further identified that a non-AUG uORF within the 5' untranslated region of γ-globin serves as a barrier for translation, which is bypassed upon PRMT1 deficiency. Finally, we found that this novel mechanism of γ-globin suppression could be pharmacologically targeted by the PRMT1 inhibitor, furamidine dihydrochloride. These data raise new questions regarding methyltransferase function and may offer a new therapeutic direction for β-hemoglobinopathies.
Keywords: protein arginine methyltransferase 1 (PRMT1); translation control; upstream open reading frame (uORF); β-hemoglobinopathies; γ-globin.
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