General rules for functional microRNA targeting — VERY interesting

I find this paper [see attached] to be extremely interesting and timely.  It wasn’t long ago that this whole crazy idea was soundly rejected by many. How on earth could small RNAs (18-22 nucleotides) be proposed to target and block translation of (subsets of) hundreds of mRNA molecules –– to keep the gene from getting expressed as a functional protein?  In other words, we have DNA sending its message via RNA to be translated into protein, whereas these micro-RNAs are preventing this from occurring.  This is called RNA-interference and is one form of “Epigenetics” –– the other accepted forms (to date) include DNA methylation, histone modifications, and chromatin remodeling.


The functional rules for microRNA (miRNA) targeting remain controversial –– despite their apparent (or possible) biological importance. They are important because only a small fraction of distinct interactions, called “site-types“, have been examined –– among an astronomical number of likely “site-types” that can occur between miRNAs and their target mRNAs.


To systematically discover functional site-types, and to evaluate various contradicting rules reported previously, authors herein used large-scale transcriptome data and statistically examined whether each (of approximately 2 billion site-types) is enriched in differentially downregulated mRNAs that respond to over-expressed miRNAs. Accordingly, they identified seven non-canonical functional site-types, most of which are novel; the remaining four canonical site-types are already established.


Authors also removed numerous false positives reported by previous studies. Extensive experimental validation –– including significantly elevated 3′-untranslated region (UTR) sequence conservation –– indicate that these non-canonical site types might well have biologically relevant roles. Authors conclude that this expanded catalog of functional site-types –– suggests that Gene Regulatory Networks that are controlled by miRNAs may be far more complex than currently understood…!!


Nat Genet Dec 2o16; 48: 1517-1526

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