title: A pre-microRNA-149 (miR-149) genetic variation affects miR-149 maturation and its ability to regulate the Puma protein in apoptosis.
abstract: MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that function as negative regulators of gene expression. They are transcribed from endogenous DNA and form hairpin structures (termed as pre-miRNAs) that are processed to form mature miRNAs. It remains largely unknown as to the molecular consequences of the natural genetic variation in pre-miRNAs. Here, we report that an A→G polymorphism (rs71428439) is located in Homo sapiens miR-149 stem-loop region. This polymorphism results in a change in the structure of the miR-149 precursor. Our results showed that the genotype distribution of this polymorphism in myocardial infarction cases was significantly different from that in the control subjects. We examined the biological significance of this polymorphism on the production of mature miR-149, and we observed that the G-allelic miR-149 precursor displayed a lower production of mature miR-149 compared with the A-allelic one. Further investigations disclosed that miR-149 could withstand mitochondrial fission and apoptosis through targeting the pro-apoptotic factor p53-up-regulated modulator of apoptosis (Puma). Enforced expression of miR-149 promoted cell survival, whereas knockdown of miR-149 rendered cells to be sensitive to apoptotic stimulation. Intriguingly, the A to G variation led pre-miR-149 to elicit an attenuated effect on the inhibition of mitochondrial fission and apoptosis. Finally, this polymorphism exerts its influence on cardiac function in the mouse model of myocardial infarction. These data suggest that this polymorphism in the miR-149 precursor may result in important phenotypic traits of myocardial infarction. Our findings warrant further investigations on the relationship between miR-149 polymorphism and myocardial infarction.
authors.affiliation: From the Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Su-Ling
authors.initials: SL
authors.lastname: Ding
authors.forename: Jian-Xun
authors.initials: JX
authors.lastname: Wang
authors.forename: Jian-Qin
authors.initials: JQ
authors.lastname: Jiao
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Qun-Yong
authors.initials: QY
authors.lastname: Zhou
authors.forename: Dong-Feng
authors.initials: DF
authors.lastname: Gu
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C551557:MIRN149 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D053148:Caspase 3
keywords: Cardiovascular Disease; Genetic Polymorphism; Human Genetics; MicroRNA; Mitochondrial Apoptosis