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The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis
- Source :
- Molecular and Cellular Biology
- Publication Year :
- 2018
-
Abstract
- Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear.<br />Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear. N6-Methyladenosine (m6A) posttranscriptional RNA modification, whose methylation and demethylation are performed by respective enzyme molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N6-adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like 3 (METTL3), and METTL14 positively controls adipogenesis by promoting cell cycle transition in MCE during adipogenesis. WTAP, coupled with METTL3 and METTL14, is increased and distributed in nucleus by the induction of adipogenesis dependently on RNA in vitro. Knockdown of each of these three proteins leads to cell cycle arrest and impaired adipogenesis associated with suppression of cyclin A2 upregulation during MCE, whose knockdown also impairs adipogenesis. Consistent with this, Wtap heterozygous knockout mice are protected from diet-induced obesity with smaller size and number of adipocytes, leading to improved insulin sensitivity. These data provide a mechanism for adipogenesis through the WTAP-METTL3-METTL14 complex and a potential strategy for treatment of obesity and associated disorders.
- Subjects :
- 0301 basic medicine
obesity
Cell cycle checkpoint
Mitosis
Cell Count
Cell Cycle Proteins
Biology
adipocyte
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
3T3-L1 Cells
Adipocytes
Animals
Humans
RNA, Messenger
RNA Processing, Post-Transcriptional
Molecular Biology
Cell Size
Cell Nucleus
Mice, Knockout
Gene knockdown
Adipogenesis
diabetes
Methyltransferase complex
RNA
Nuclear Proteins
Cell Differentiation
Cell Biology
Cell Cycle Checkpoints
Methyltransferases
Cell cycle
Cell biology
Clone Cells
DNA-Binding Proteins
030104 developmental biology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
RNA Splicing Factors
Insulin Resistance
Carrier Proteins
Energy Metabolism
Cyclin A2
Research Article
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 38
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- Molecular and cellular biology
- Accession number :
- edsair.doi.dedup.....bcaca2c2b52f4b1616f7f53083f56089