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Allele‐Dependent miRNA Regulation of MMP9 and the Importance of Coding Region Polymorphisms in Gene Expression
Author(s) -
Duellman Tyler,
Warren Chris,
Yang Jay
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.663.18
Subject(s) - biology , single nucleotide polymorphism , microrna , gene , coding region , genetics , allele , mmp9 , microbiology and biotechnology , genotype , downregulation and upregulation
During the course of a study investigating the functional consequences of Matrix Metalloproteinase 9 (MMP9) single nucleotide polymorphisms (SNPs), as part of a case: control genotype correlation analysis with abdominal aortic aneurysm, we identified a SNP, rs41427445 (N38S), which resulted in a profound decrease in the amount of secreted MMP9 protein. Bioinformatic analysis of miRNAs targeting polymorphic sites within the coding region of MMP9 indicated a number of miRNAs that targeted polymorphic sites in an allele‐dependent fashion potentially altering post‐transcriptional regulation of the polymorphic mRNA. The analysis indicated the presence of two miRNAs, hsa‐miR‐671–3p and hsa‐miR‐657 that preferentially targeted the N38S mRNA with higher affinity than wild type MMP9 mRNA. miR inhibitors (antisense oligomers) and “silent mutagenesis” (disruption of miRNA affinity but maintenance of amino acid sequence) validated these dual miRNAs as mediating the suppression of N38S‐MMP9 expression in an allelic‐dependent fashion revealing miRNA targeting the coding region as novel regulators of MMP9 expression.