m6A modification promotes miR-133a repression during cardiac development and hypertrophy via IGF2BP2

Both N6-methyladenosine (m6A) RNA modification and microRNAs (miRNAs) are common regulatory mechanisms for gene post-transcription by modulating mRNA stability and translation. They also share the same 3′-untranslated regions (UTRs) regions for their target gene. However, little is known about their...

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Bibliographic Details
Published in:Cell death discovery 2021-06, Vol.7 (1), p.157-157, Article 157
Main Authors: Qian, Benheng, Wang, Ping, Zhang, Donghong, Wu, Lianpin
Format: Article
Language:English
Subjects:
3' Untranslated regions
631/136/2091
631/208/176/2016
692/699/75/74/1540
Apoptosis
Argonaute 2 protein
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Conserved sequence
Dioxygenase
Gene expression
Heart
Hypertrophy
Immunofluorescence
Immunoprecipitation
Insulin
Ketoglutaric acid
Life Sciences
MicroRNAs
miRNA
mRNA stability
N6-methyladenosine
Nucleotide sequence
Post-transcription
RNA modification
Stem Cells
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Summary:Both N6-methyladenosine (m6A) RNA modification and microRNAs (miRNAs) are common regulatory mechanisms for gene post-transcription by modulating mRNA stability and translation. They also share the same 3′-untranslated regions (UTRs) regions for their target gene. However, little is known about their potential interaction in cell development and biology. Here, we aimed to investigate how m6A regulates the specific miRNA repression during cardiac development and hypertrophy. Our multiple lines of bioinformatic and molecular biological evidence have shown that m6A modification on cardiac miR-133a target sequence promotes miR-133a repressive effect via AGO2-IGF2BP2 (Argonaute 2—Insulin-like growth factor 2 mRNA binding protein 2) complex. Among 139 cardiac miRNAs, only the seed sequence of miR-133a was inversely complement to m6A consensus motif “GGACH” by sequence alignment analysis. Immunofluorescence staining, luciferase reporter, and m6A-RIP (RNA immunoprecipitation) assays revealed that m6A modification facilitated miR-133a binding to and repressing their targets. The inhibition of the miR-133a on cardiac proliferation and hypertrophy could be prevented by silencing of Fto (FTO alpha-ketoglutarate dependent dioxygenase) which induced m6A modification. IGF2BP2, an m6A binding protein, physically interacted with AGO2 and increased more miR-133a accumulation on its target site, which was modified by m6A. In conclusion, our study revealed a novel and precise regulatory mechanism that the m6A modification promoted the repression of specific miRNA during heart development and hypertrophy. Targeting m6A modification might provide a strategy to repair hypertrophic gene expression induced by miR-133a.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-021-00552-7