| 研究実績の概要 |
Developmental events often take place sequentially under the control of clock-like mechanisms, as exemplified by the cerebral cortex, which is formed by sequential generation of diverse neurons owing to the temporal pattern of neural stem cell (NSC) state. While the temporal NCS state has been regarded as mainly defined by transcription and epigenetic modifications, it remains elusive what drives its progression. I proved that translational control of histone H3K27me3 modifiers is part of this developmental clock. I first showed that the temporal pattern of NSC state is represented by genome-wide H3K27me3 but not H3K4me3 modification. I identified that Fbl, a ribosomal RNA methyltransferase, as an upstream regulator of H3K27me3 modification. Fbl selectively regulates the translation of mRNAs encoding both the Ezh2 methyltransferase and Kdm6b demethylase of H3K27me3. Concomitantly, Fbl depletion compromised change in H3K27me3 pattern and delayed the temporal progression of NSC transcriptional state in an intrinsic manner. These defects are phenocopied by the simultaneous inhibition of H3K27me3 methyltransferase and demethylase, but not either of them, indicating the role of Fbl in the global epigenetic rearrangement. Selective acceleration of Ezh2 and Kdm6b translation by Fbl may be exerted via a cap-independent mechanism of their 5′untranslated region. These results thus propose that Fbl drives the intrinsic clock through the translational enhance of H3K27me3 modifiers along the regulatory axis of Fbl-H3K27me3 modification to define the NSC temporal state.
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