Selective translation of epigenetic modifiers affects the temporal pattern and differentiation of neural stem cells

Quan Wu,Fumio Matsuzaki,Taeko Suetsugu,Yuichi Shichino,Ayaka Omori,Shintaro Iwasaki,Hiroshi Kiyonari,Takaya Abe

doi:10.1038/s41467-022-28097-y

Quan Wu, Fumio Matsuzaki + Show 6 more

Open Access

https://doi.org/10.1038/s41467-022-28097-y

Copy DOI

Abstract

The cerebral cortex is formed by diverse neurons generated sequentially from neural stem cells (NSCs). A clock mechanism has been suggested to underlie the temporal progression of NSCs, which is mainly defined by the transcriptome and the epigenetic state. However, what drives such a developmental clock remains elusive. We show that translational control of histone H3 trimethylation in Lys27 (H3K27me3) modifiers is part of this clock. We find that depletion of Fbl, an rRNA methyltransferase, reduces translation of both Ezh2 methyltransferase and Kdm6b demethylase of H3K27me3 and delays the progression of the NSC state. These defects are partially phenocopied by simultaneous inhibition of H3K27me3 methyltransferase and demethylase, indicating the role of Fbl in the genome-wide H3K27me3 pattern. Therefore, we propose that Fbl drives the intrinsic clock through the translational enhancement of the H3K27me3 modifiers that predominantly define the NSC state.

Highlights

The cerebral cortex is formed by diverse neurons generated sequentially from neural stem cells (NSCs)
The cell was lysed and mRNAs from the cell were reverse-transcribed by priming with a ploy-T primer, which contains a specific cell barcode for cell identification and a unique molecular index (UMI) for mRNA identification
These results indicated that our transcriptome data are of high quality enough to perform temporal analyses at the single-cell transcriptome level

Summary

Introduction

The cerebral cortex is formed by diverse neurons generated sequentially from neural stem cells (NSCs). A clock mechanism has been suggested to underlie the temporal progression of NSCs, which is mainly defined by the transcriptome and the epigenetic state. What drives such a developmental clock remains elusive. The sequential generation of diverse neurons from a small population of neural stem cells (NSCs) in a highly orchestrated order in the mammalian cerebral cortex may be controlled by a developmental clock. We show that Fbl, an rRNA methyltransferase, is required for temporal progression and differentiation of NSCs. Fbl potentially drives the developmental clock by promoting the translation of the key modifiers of H3K27me[3] in NSCs

Methods

Results

Conclusion