Needles in the genetic haystack of lipid disorders: single nucleotide polymorphisms in the microRNA regulome

Abstract

This article is available online at http://www.jlr.org inhibits protein translation. Although mammalian miRNAs were not discovered until a decade ago ( 2 ), they have rapidly emerged as important posttranscriptional regulators of gene expression in a wide variety of biological pathways ( 3 ). Moreover, miRNAs have been demonstrated to be i ) stable plasma biomarkers of physiological status ( 4,5 ), ii ) novel intercellular signaling molecules ( 6 ), iii ) etiological factors in complex diseases ( 7 ), and iv ) promising therapeutic targets ( 8,9 ).In 2002, miR-122 was found to be the most abundant miRNA in the liver, accounting for greater than 70% of all hepatic miRNA expression ( 2 ). More recent, high-throughput small RNA sequencing (smRNA-seq) studies have confi rmed this fi nding and, notably, have not detected miR-122 in any other cell type ( 10 ). Circulating levels of miR-122 have been identifi ed as a clinically relevant biomarker of liver injury ( 11, 12 ), cirrhosis ( 13 ), necroinfl ammation ( 14 ), and hyperlipidemia ( 15 ). In 2005, miR-122 was also shown to directly promote the replication of the hepatitis C virus (HCV) ( 16 ). Subsequently, it was demonstrated that inhibition of miR-122 by a locked nucleic acid (LNA) antisense oligonucleotide diminishes HCV viremia in chimpanzees ( 17 ). The anti-miR-122 LNA molecule (known as Miravirsen) has since advanced to phase II human clinical trials for hepatitis C treatment, and it appears to induce a potent antiviral effect in the absence of evident liver or cardiac toxicities ( 18 ).miR-122 was also the fi rst miRNA identifi ed as a regulator of lipid metabolism ( 19 ). In 2006, antisense oligonucleotide-mediated inhibition of miR-122 (ASO-miR-122) in mice reduced plasma cholesterol levels, decreased hepatic lipid synthesis, and enhanced hepatic fatty acid oxidation ( 19 ). Moreover, the ASO-miR-122 was also able to reverse the effects of diet-induced obesity by reducing hepatic steatosis. Abbreviations: LRE, long-range regulatory element; miRNA (miR), microRNA; miR-122, miRNA-122; pre-miRNA, miRNA precursor; primiRNA, primary miRNA; ORF, open reading frame; RISC, RNA-induced silencing complex; SNP, single nucleotide polymorphism; TF, transcriptional factor; UTR, untranslated region.

Deep sequencing shows microRNA involvement in bovine mammary gland adaptation to diets supplemented with linseed oil or safflower oil

“…MicroRNAs (miRNAs) are small regulatory RNA molecules that have been shown to be involved in a wide range of biological pathways by modulating expression of specific mRNAs [ 20 ]. The role of miRNAs in lipid metabolism has been recently demonstrated [ 21 ] and lipid homeostasis was found to be governed in part by an intricate web of miRNA activity [ 22 ]. In bovine mammary gland, the expression of numerous miRNAs was increased during the postpartum or the early lactation periods as compared to the dry period [ 23 ].…”

PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways

“…The PolymiRTS database currently focuses on featuring polymorphisms in miRNA seed regions and miRNA target sites. Recent studies have revealed the functional importance of genetic polymorphisms in other parts of the miRNA regulome ( 46 , 47 ). Polymorphisms in pre-miRNAs, pri-miRNAs and miRNA promoters have been associated with many diseases.…”

MicroRNAs and Drinking: Association between the Pre-miR-27a rs895819 Polymorphism and Alcohol Consumption in a Mediterranean Population

“…This approach could be much more reproducible, given that the presence or absence of an SNP in the genes encoding an miRNA does not change whether the DNA comes from leukocytes or any other type of cell. Moreover, it is known that a single miRNA can target hundreds of mRNA transcripts for either translation repression or degradation, and the detection of a polymorphism in a gene encoding a particular miRNA can affect many mRNAs and have a great influence [ 48 , 49 ]; such as an intermediate hairpin precursor miRNA (pre-miRNA), which is transported to the cytoplasm by exportin-5 and further processed by another RNase III–like enzyme, Dicer, to the mature miRNA (for a review, see Kim, 2005).…”

“…This long pri-miRNA (having several hundred nucleotides) is further processed into an intermediate hairpin precursor miRNA (pre-miRNA). The pre-miRNAs is further processed by Dicer, to the mature miRNAs [ 30 , 48 ]. Pre-miRNA polymorphisms may have an important functional role for miRNA binding and posttranscriptional regulation [ 49 ].…”