m6A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation

Jiansong Huang; Bowen Jiang; Guo-Wei Li; Dandan Zheng; Mingyi Li; Xuan Xie; Yuxiang Pan; Manyi Wei; Xiaoyan Liu; Xingyu Jiang; Xu Zhang; Li Yang; Lan Bao; Bin Wang

doi:10.1016/j.celrep.2022.111693

m⁶A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation

Cell Rep. 2022 Nov 22;41(8):111693. doi: 10.1016/j.celrep.2022.111693.

Authors

Jiansong Huang¹, Bowen Jiang¹, Guo-Wei Li², Dandan Zheng³, Mingyi Li¹, Xuan Xie¹, Yuxiang Pan¹, Manyi Wei¹, Xiaoyan Liu⁴, Xingyu Jiang⁴, Xu Zhang⁵, Li Yang⁶, Lan Bao⁷, Bin Wang⁸

Affiliations

¹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
² CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁴ Southern University of Science and Technology, Shenzhen 518055, China.
⁵ Guangdong Institute of Intelligence Science and Technology, Hengqin 519031, Zhuhai, China; Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China; Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.
⁶ Center for Molecular Medicine, Children's Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200031, China.
⁷ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: baolan@sibcb.ac.cn.
⁸ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Guangdong Institute of Intelligence Science and Technology, Hengqin 519031, Zhuhai, China. Electronic address: wangbin@gdiist.cn.

PMID: 36417851
DOI: 10.1016/j.celrep.2022.111693

Abstract

Long intergenic noncoding RNAs (lincRNAs) are crucial regulators in numerous biological processes. However, the functions and mechanisms of m⁶A-modified lincRNAs in neuronal development remain unclear. Here, we report an m⁶A-modified lincRNA, Dppa2 upstream binding RNA (Dubr), abundantly expressed at the early developmental stage of dorsal root ganglion (DRG) and cerebral cortex. Silencing Dubr impairs axon elongation of DRG neurons and axon projection and migration of cortical neurons, whereas lacking m⁶A modification of Dubr fully loses its functions. Mechanically, Dubr interacts with m⁶A-binding proteins, the YTHDF1/3 complex, through its m⁶A motifs to protect YTHDF1/3 from degradation via the proteasome pathway. Furthermore, Tau and Calmodulin are regulated by YTHDF1/3 and m⁶A-modified Dubr. Overexpression of YTHDF1/3 not only rescues the reduced Tau and Calmodulin but also restores axon elongation of DRG neurons by Dubr knockdown. This study uncovers a critical role of m⁶A-modified lincRNA in neuronal development by regulating the degradation of RNA-binding protein.

Keywords: CP: Molecular biology; CP: Neuroscience; Dubr; Neuronal development; YTHDF1; YTHDF3; m(6)A-modified lincRNA; mRNA translation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calmodulin / metabolism
Neurons / metabolism
Protein Biosynthesis
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism

Substances

RNA, Long Noncoding
Calmodulin
RNA-Binding Proteins