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05 31, 2018;19 (1): 68.

RNA mA methylation participates in regulation of postnatal development of the mouse cerebellum.

Chunhui Ma, Mengqi Chang, Hongyi Lv, Zhi-Wei Zhang, Weilong Zhang, Xue He, Gaolang Wu, Shunli Zhao, Yao Zhang, Di Wang, Xufei Teng, Chunying Liu, Qing Li, Arne Klungland, Yamei Niu, Shuhui Song, Wei-Min Tong
Author Information
  1. Chunhui Ma: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  2. Mengqi Chang: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  3. Hongyi Lv: BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
  4. Zhi-Wei Zhang: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  5. Weilong Zhang: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China.
  6. Xue He: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  7. Gaolang Wu: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  8. Shunli Zhao: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  9. Yao Zhang: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  10. Di Wang: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  11. Xufei Teng: BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
  12. Chunying Liu: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  13. Qing Li: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China.
  14. Arne Klungland: Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, NO-0027, Norway.
  15. Yamei Niu: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China. niuym@ibms.pumc.edu.cn. ORCID
  16. Shuhui Song: BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. songshh@big.ac.cn.
  17. Wei-Min Tong: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100005, China. wmtong@ibms.pumc.edu.cn.
PMID: 29855379 DOI: 10.1186/s13059-018-1435-z

Abstract

BACKGROUND: N-methyladenosine (mA) is an important epitranscriptomic mark with high abundance in the brain. Recently, it has been found to be involved in the regulation of memory formation and mammalian cortical neurogenesis. However, while it is now established that mA methylation occurs in a spatially restricted manner, its functions in specific brain regions still await elucidation.
RESULTS: We identify widespread and dynamic RNA mA methylation in the developing mouse cerebellum and further uncover distinct features of continuous and temporal-specific mA methylation across the four postnatal developmental processes. Temporal-specific mA peaks from P7 to P60 exhibit remarkable changes in their distribution patterns along the mRNA transcripts. We also show spatiotemporal-specific expression of mA writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in the mouse cerebellum. Ectopic expression of METTL3 mediated by lentivirus infection leads to disorganized structure of both Purkinje and glial cells. In addition, under hypobaric hypoxia exposure, Alkbh5-deletion causes abnormal cell proliferation and differentiation in the cerebellum through disturbing the balance of RNA mA methylation in different cell fate determination genes. Notably, nuclear export of the hypermethylated RNAs is enhanced in the cerebellum of Alkbh5-deficient mice exposed to hypobaric hypoxia.
CONCLUSIONS: Together, our findings provide strong evidence that RNA mA methylation is controlled in a precise spatiotemporal manner and participates in the regulation of postnatal development of the mouse cerebellum.

Keywords

ALKBH5 Cerebellar development METTL3 N6-methyladenosine RNA methylation

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Grants

  1. 31471288/National Natural Science Foundation of China
  2. 31471343/National Natural Science Foundation of China
  3. 2016-I2M-1-004/CAMS Initiative for Innovative Medicine
  4. 2016-I2M-2-001/CAMS Initiative for Innovative Medicine
  5. 2017141/Youth Innovation Promotion Association of the Chinese Academy of Sciences

MeSH Term

Adenosine
AlkB Homolog 5, RNA Demethylase
Animals
Cell Hypoxia
Cell Line
Cerebellum
Female
HEK293 Cells
Humans
Male
Methylation
Methyltransferases
Mice
Mice, Inbred C57BL
Mice, Knockout
RNA

Chemicals

RNA
N-methyladenosine
ALKBH5 protein, mouse
AlkB Homolog 5, RNA Demethylase
Methyltransferases
Mettl3 protein, mouse
Adenosine
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GSA: CRA000472 (cerebellum_m6A)
BioProject: PRJCA000543 (mouse cerebellum m6A RNA methylation)

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