Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3' untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes.
Animal microRNAs (miRNAs) regulate gene expression through base pairing to their targets within the 3' untranslated region (UTR) of protein-coding genes. Single-nucleotide polymorphisms (SNPs) located within such target sites can affect miRNA regulation. We mapped annotated SNPs onto a collection of experimentally supported human miRNA targets. Of the 143 experimentally supported human target sites, 9 contain 12 SNPs. We further experimentally investigated one of these target sites for hsa-miR-155, within the 3' UTR of the human AGTR1 gene that contains SNP rs5186. Using reporter silencing assays, we show that hsa-miR-155 down-regulates the expression of only the 1166A, and not the 1166C, allele of rs5186. Remarkably, the 1166C allele has been associated with hypertension in many studies. Thus, the 1166C allele may be functionally associated with hypertension by abrogating regulation by hsa-miR-155, thereby elevating AGTR1 levels. Since hsa-miR-155 is on chromosome 21, we hypothesize that the observed lower blood pressure in trisomy 21 is partially caused by the overexpression of hsa-miR-155 leading to allele-specific underexpression of AGTR1. Indeed, we have shown in fibroblasts from monozygotic twins discordant for trisomy 21 that levels of AGTR1 protein are lower in trisomy 21.
Department of Genetics, School of Medicine, University of Pennsylvania, PA, USA, and University Hospitals of Geneva, Switzerland.
Praveen
P
Sethupathy
Christelle
C
Borel
Maryline
M
Gagnebin
Gregory R
GR
Grant
Samuel
S
Deutsch
Terry S
TS
Elton
Artemis G
AG
Hatzigeorgiou
Stylianos E
SE
Antonarakis
D020413:3' Untranslated Regions; D001483:Base Sequence; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D015203:Reproducibility of Results
D020413:3' Untranslated Regions; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D044140:Receptor, Angiotensin, Type 1