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An evolutionary perspective of animal microRNAs and their targets.

Shomron N, Golan D, Hornstein E - J. Biomed. Biotechnol. (2009)

Bottom Line: MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through translational inhibition or mRNA degradation by binding to sequences on the target mRNA. miRNA regulation appears to be the most abundant mode of posttranscriptional regulation affecting approximately 50% of the transcriptome. miRNA genes are often clustered and/or located in introns, and each targets a variable and often large number of mRNAs.Here we discuss the genomic architecture of animal miRNA genes and their evolving interaction with their target mRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell & Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. nshomron@post.tau.ac.il

ABSTRACT
MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through translational inhibition or mRNA degradation by binding to sequences on the target mRNA. miRNA regulation appears to be the most abundant mode of posttranscriptional regulation affecting approximately 50% of the transcriptome. miRNA genes are often clustered and/or located in introns, and each targets a variable and often large number of mRNAs. Here we discuss the genomic architecture of animal miRNA genes and their evolving interaction with their target mRNAs.

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The number of predicted conserved miRNA target sites. (a) Predicted number of conserved targets, conserved target sites and poorly conserved sites of human miRNAs (based on TargetScanS). (b) The number of predicted conserved miRNA targets was divided according to the conservation level of the miRNA itself (H, Human; P, Chimp; M, Mouse; R, Rat; D, Dog; C, Chicken; based on TargetScanS). Shaded in red/green are the regions with the largest/least number of targets (resp.). Extreme numbers of targets are boxed and are discussed in the text.
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fig3: The number of predicted conserved miRNA target sites. (a) Predicted number of conserved targets, conserved target sites and poorly conserved sites of human miRNAs (based on TargetScanS). (b) The number of predicted conserved miRNA targets was divided according to the conservation level of the miRNA itself (H, Human; P, Chimp; M, Mouse; R, Rat; D, Dog; C, Chicken; based on TargetScanS). Shaded in red/green are the regions with the largest/least number of targets (resp.). Extreme numbers of targets are boxed and are discussed in the text.

Mentions: Conserved complementarities to a minimal hexamer region (matching nt 2–7 of the miRNA) [8] indicates that once a seed match emerges, it becomes functional. If the binding is preferentially beneficial, it might serve as a favorable and directional intermediate species. Within Tetrapods, the average number of predicted conserved sites per miRNA is at the range of 200 (Figure 3(a), TargetScanS, plotted for Human miRNAs). However, the number of targets is skewed to the higher values, while the upper and lower 10-percentiles regulate more than 450 or less than 50 genes, respectively (also see [87, 88]). Comparative genomics suggests that ancient miRNAs have on average twofold more targets than newly generated ones (compare 453 to 194, resp.). Some discrepancies result from misestimating miRNA antiquity or overlapping miRNA functional sites. Specifically, the age of some miRNA genes might have been misestimated, as cross-species orthologues searches are not exhausted yet. miR-761, for example, identified only in mouse [57] is in fact conserved in six other mammals (including human and opossum; see [89] also see miRviewer at http://people.csail.mit.edu/akiezun/miRviewer). Alternatively, overlapping functional sites shared by miRNAs and other regulatory factors may bias the distribution of targets. For example, pre-existing “scaffolds” of other regulatory systems could serve as anchors for miRNA binding. In the case of miR-16, a component of the AU-rich mediated deregulation of mRNA stability [90], the miRNA is a late addition onto a mechanism that was probably functional in the common ancestor of yeast [91], before the innovation of miRNAs. In this train of thought, some transcriptional termination or pause sites [92, 93] overlap with miRNA seed-matches (miR-525 and miR-488). In human, Alu transposable elements exhibit complementarities in some of their regions to almost 30 human miRNAs [94]. In other instances, the attempt to avoid specific protein binding domains in the 3′ UTRs may expel miRNA binding sites. For example, 3′ UTRs may avoid miR-518a seed (which has only 26 predicted conserved targets) because it perfectly matches the proline and acidic rich (PAR) protein binding sequence [95]. Other miRNA interference events may involve binding to promoters via antisense transcription, which is estimated to be as common as 15% in the human genome [96]. Overlapping sequences as such might coincide with promiscuous promoter-associated functions of small RNAs [36] or increase in transcription [97]. Plausibly a selective pressure to avoid the binding of the aryl hydrocarbon receptor (AhR) [98] onto miR-521 sites (AhR and miR-521 share the same sequence) may explain how miRNAs of similar antiquity and A/U content (compare to miR-520 h) dramatically vary in their predicted numbers of conserved targets (compare 8 to >400, resp.; both miRNAs are part of the same primary transcript, BF773110). It is noteworthy that the low number of miR-521 targets cannot be explained by a conflict of expression in a broad set of tissues since miR-521 is expressed only in placenta.


An evolutionary perspective of animal microRNAs and their targets.

Shomron N, Golan D, Hornstein E - J. Biomed. Biotechnol. (2009)

The number of predicted conserved miRNA target sites. (a) Predicted number of conserved targets, conserved target sites and poorly conserved sites of human miRNAs (based on TargetScanS). (b) The number of predicted conserved miRNA targets was divided according to the conservation level of the miRNA itself (H, Human; P, Chimp; M, Mouse; R, Rat; D, Dog; C, Chicken; based on TargetScanS). Shaded in red/green are the regions with the largest/least number of targets (resp.). Extreme numbers of targets are boxed and are discussed in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2743850&req=5

fig3: The number of predicted conserved miRNA target sites. (a) Predicted number of conserved targets, conserved target sites and poorly conserved sites of human miRNAs (based on TargetScanS). (b) The number of predicted conserved miRNA targets was divided according to the conservation level of the miRNA itself (H, Human; P, Chimp; M, Mouse; R, Rat; D, Dog; C, Chicken; based on TargetScanS). Shaded in red/green are the regions with the largest/least number of targets (resp.). Extreme numbers of targets are boxed and are discussed in the text.
Mentions: Conserved complementarities to a minimal hexamer region (matching nt 2–7 of the miRNA) [8] indicates that once a seed match emerges, it becomes functional. If the binding is preferentially beneficial, it might serve as a favorable and directional intermediate species. Within Tetrapods, the average number of predicted conserved sites per miRNA is at the range of 200 (Figure 3(a), TargetScanS, plotted for Human miRNAs). However, the number of targets is skewed to the higher values, while the upper and lower 10-percentiles regulate more than 450 or less than 50 genes, respectively (also see [87, 88]). Comparative genomics suggests that ancient miRNAs have on average twofold more targets than newly generated ones (compare 453 to 194, resp.). Some discrepancies result from misestimating miRNA antiquity or overlapping miRNA functional sites. Specifically, the age of some miRNA genes might have been misestimated, as cross-species orthologues searches are not exhausted yet. miR-761, for example, identified only in mouse [57] is in fact conserved in six other mammals (including human and opossum; see [89] also see miRviewer at http://people.csail.mit.edu/akiezun/miRviewer). Alternatively, overlapping functional sites shared by miRNAs and other regulatory factors may bias the distribution of targets. For example, pre-existing “scaffolds” of other regulatory systems could serve as anchors for miRNA binding. In the case of miR-16, a component of the AU-rich mediated deregulation of mRNA stability [90], the miRNA is a late addition onto a mechanism that was probably functional in the common ancestor of yeast [91], before the innovation of miRNAs. In this train of thought, some transcriptional termination or pause sites [92, 93] overlap with miRNA seed-matches (miR-525 and miR-488). In human, Alu transposable elements exhibit complementarities in some of their regions to almost 30 human miRNAs [94]. In other instances, the attempt to avoid specific protein binding domains in the 3′ UTRs may expel miRNA binding sites. For example, 3′ UTRs may avoid miR-518a seed (which has only 26 predicted conserved targets) because it perfectly matches the proline and acidic rich (PAR) protein binding sequence [95]. Other miRNA interference events may involve binding to promoters via antisense transcription, which is estimated to be as common as 15% in the human genome [96]. Overlapping sequences as such might coincide with promiscuous promoter-associated functions of small RNAs [36] or increase in transcription [97]. Plausibly a selective pressure to avoid the binding of the aryl hydrocarbon receptor (AhR) [98] onto miR-521 sites (AhR and miR-521 share the same sequence) may explain how miRNAs of similar antiquity and A/U content (compare to miR-520 h) dramatically vary in their predicted numbers of conserved targets (compare 8 to >400, resp.; both miRNAs are part of the same primary transcript, BF773110). It is noteworthy that the low number of miR-521 targets cannot be explained by a conflict of expression in a broad set of tissues since miR-521 is expressed only in placenta.

Bottom Line: MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through translational inhibition or mRNA degradation by binding to sequences on the target mRNA. miRNA regulation appears to be the most abundant mode of posttranscriptional regulation affecting approximately 50% of the transcriptome. miRNA genes are often clustered and/or located in introns, and each targets a variable and often large number of mRNAs.Here we discuss the genomic architecture of animal miRNA genes and their evolving interaction with their target mRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell & Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. nshomron@post.tau.ac.il

ABSTRACT
MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through translational inhibition or mRNA degradation by binding to sequences on the target mRNA. miRNA regulation appears to be the most abundant mode of posttranscriptional regulation affecting approximately 50% of the transcriptome. miRNA genes are often clustered and/or located in introns, and each targets a variable and often large number of mRNAs. Here we discuss the genomic architecture of animal miRNA genes and their evolving interaction with their target mRNAs.

Show MeSH