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MicroRNA Mechanisms of Action: What have We Learned from Mice?

Jin HY, Xiao C - Front Genet (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute La Jolla, CA, USA ; Kellogg School of Science and Technology, The Scripps Research Institute La Jolla, CA, USA.

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A follow-up study employing temporal dissection of zebrafish development seems to reconcile these two opposite observations by revealing that translational repression precedes target mRNA decay, and suggesting that the immediate outcome of miRNA-target mRNA interaction is translation inhibition but mRNA degradation can follow (Bazzini et al., )... Similarly, re-analysis of the previous datasets from cultured cell lines transiently transfected with synthetic miRNA mimics also found that translation repression precedes mRNA degradation (Larsson and Nadon, )... However, the model miRNA used in the aforementioned zebrafish study, miR-430, is unique in that its expression is rapidly induced and reaches millions of copies per cell in a few hours after fertilization... As an extreme example, miR-122 is expressed at the estimated level of 5 × 10 copies per cell in hepatocytes (Chang et al., ; Jopling et al., )... This is still about 20 times lower than the million-copy-per-cell expression level of miR-430 in zebrafish embryos... It is conceivable that mRNA degradation gets rid of target gene mRNAs in a non-reversible way and provides an efficient way for cell fate determination, while translation repression is immediate, transient, and reversible, which is more suitable for differentiated cells to respond to environmental stresses... Several groups independently observed that target genes of miR-17~92 (Lu et al., ; Shan et al., ; Jiang et al., ; Bian et al., ; Danielson et al., ; Jin et al., ), miR-214 (Aurora et al., ; Wang et al., ; Li et al., ), miR-143/145 (Boettger et al., ; Jordan et al., ; Caruso et al., ; Dahan et al., ), and miR-146 (Boldin et al., ; Guo et al., ; Stickel et al., ) tend to be regulated at the translational level, but target genes of miR-122 (Hsu et al., ; Tsai et al., ), miR-140 (Miyaki et al., ; Nakamura et al., ) and miR-142 (Chapnik et al., ; Kramer et al., ; Sun et al., ) are often regulated by mRNA degradation... Interestingly, among miR-155 target genes, some are predominantly regulated by translation repression, some are mainly regulated by mRNA degradation, while the others are regulated by both mechanisms (Vigorito et al., ; Dorsett et al., ; Lu et al.,, ; O'Connell et al.,, ; Dudda et al., ; Escobar et al., ; Hu et al., ; Jin et al., ; Wang et al., ), suggesting that different target genes of the same miRNA can be regulated through different mechanisms even in the same cell... In the same vein, translatome analysis is more appropriate for measuring the global effect of a miRNA on its target genes, while transcriptome analysis often failed to identify any significant effect of miRNA deletion on its target genes, despite the obvious functional consequences in mutant mice (Matkovich et al., ; Boldin et al., ; Jiang et al., ; Agudo et al., ; Sullivan et al., ; Yuan et al., )... In the broader context of gene expression regulation, accumulating evidence shows that proteome and transcriptome are not sufficiently correlated to act as proxies for each other (Payne, ). miRNA-mediated translation regulation may play an important role in the de-coupling of translatome from transcriptome... We speculate that miRNAs emerged during evolution to increase the complexity of gene regulation, thereby contributing to the diversity of organisms.

No MeSH data available.


Contribution of translation repression and mRNA degradation to miRNA regulation of target gene expression in primary cells and tissues from miRNA mutant mice. Number in parentheses indicates the number of genes in each category. See also Table S1 for detailed information.
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Figure 1: Contribution of translation repression and mRNA degradation to miRNA regulation of target gene expression in primary cells and tissues from miRNA mutant mice. Number in parentheses indicates the number of genes in each category. See also Table S1 for detailed information.

Mentions: Here we sought to summarize the relative contribution of translation repression and mRNA degradation to miRNA regulation of functional targets in miRNA mutant mice. We focused on miRNA target genes whose protein and mRNA levels were measured concurrently in primary cells or tissues from mutant mice with genetic ablation or transgenic expression of individual miRNA genes. This includes a total of 159 target genes from 77 miRNA mutant mice (Table S1; Zhao et al., 2005, 2007; Lu et al., 2007, 2009, 2014; van Rooij et al., 2007; Vigorito et al., 2007; Dorsett et al., 2008; Liu et al., 2008, 2011, 2012, 2014; Wang et al., 2008, 2013a,b, 2014, 2015a,b; Boettger et al., 2009; Callis et al., 2009; O'Connell et al., 2009, 2010; Poy et al., 2009; Shan et al., 2009; Williams et al., 2009; Xin et al., 2009; Miyaki et al., 2010; Patrick et al., 2010; Yu et al., 2010; Biton et al., 2011; Boldin et al., 2011; Dunand-Sauthier et al., 2011; Jiang et al., 2011; Jordan et al., 2011; Ma et al., 2011, 2013; Nakamura et al., 2011; Sanuki et al., 2011; Shibata et al., 2011; Aurora et al., 2012; Callegari et al., 2012; Caruso et al., 2012; Dong et al., 2012; Gurha et al., 2012; Horie et al., 2012, 2013; Hsu et al., 2012; Liang et al., 2012, 2015; Mori et al., 2012; Tsai et al., 2012; Ucar et al., 2012; Wei et al., 2012, 2014; Zhuang et al., 2012; Belkaya et al., 2013; Bian et al., 2013; Danielson et al., 2013; Dorhoi et al., 2013; Dudda et al., 2013; Gebeshuber et al., 2013; Guo et al., 2013; Hasuwa et al., 2013; Heidersbach et al., 2013; Henao-Mejia et al., 2013; Khan et al., 2013; Mok et al., 2013; Song et al., 2013, 2014; Stadthagen et al., 2013; Tan et al., 2013; Wystub et al., 2013; Agudo et al., 2014; Ahmed et al., 2014; Burger et al., 2014; Chapnik et al., 2014; Dahan et al., 2014; Escobar et al., 2014; Giusti et al., 2014; Hu et al., 2014; Krzeszinski et al., 2014; Latreille et al., 2014; Pan et al., 2014; Stickel et al., 2014; Cushing et al., 2015; Jin et al., 2015; Kosaka et al., 2015; Kramer et al., 2015; Li et al., 2015a,b,c; Parchem et al., 2015; Sullivan et al., 2015; Sun et al., 2015; Tung et al., 2015; Xu et al., 2015; Yan et al., 2015; Zhang et al., 2015). Our analysis showed that 48% target genes are predominantly regulated by translation repression (76/159), 29% are regulated mainly by mRNA degradation (46/159), and 23% are regulated by both (37/159) (Figure 1). It is still unclear what determines the dominant mode of miRNA mechanism of action. As most of these studies measured target gene mRNA and protein levels under steady-state conditions, we speculate that differences in miRNA mechanism of action are not solely determined by the expression kinetics of miRNA or target mRNAs (Bazzini et al., 2012; Béthune et al., 2012; Djuranovic et al., 2012), but are instead attributed to cell type-, target mRNA-, or even miRNA-specific factors. Interestingly, almost all target genes identified in developing cells or tissues are mainly regulated by mRNA degradation, such as day 0 or day 2.5 cardiac cells (Heidersbach et al., 2013; Wei et al., 2014), embryonic stem cell-derived neurons (Tung et al., 2015), thymocytes (Belkaya et al., 2013; Henao-Mejia et al., 2013; Burger et al., 2014), bone marrow cells (Song et al., 2013), embryonic heart (Wystub et al., 2013; Liang et al., 2015), embryonic yolk sac (Wang et al., 2008), embryonic and neonatal epithelium (Ahmed et al., 2014), and fetal liver (Patrick et al., 2010). This is in sharp contrast to target genes identified in terminally differentiated cells, which are predominantly regulated by translation repression. It is conceivable that mRNA degradation gets rid of target gene mRNAs in a non-reversible way and provides an efficient way for cell fate determination, while translation repression is immediate, transient, and reversible, which is more suitable for differentiated cells to respond to environmental stresses. Our analysis also suggests miRNA-specific functional consequences. Several groups independently observed that target genes of miR-17~92 (Lu et al., 2007; Shan et al., 2009; Jiang et al., 2011; Bian et al., 2013; Danielson et al., 2013; Jin et al., 2015), miR-214 (Aurora et al., 2012; Wang et al., 2013b; Li et al., 2015b), miR-143/145 (Boettger et al., 2009; Jordan et al., 2011; Caruso et al., 2012; Dahan et al., 2014), and miR-146 (Boldin et al., 2011; Guo et al., 2013; Stickel et al., 2014) tend to be regulated at the translational level, but target genes of miR-122 (Hsu et al., 2012; Tsai et al., 2012), miR-140 (Miyaki et al., 2010; Nakamura et al., 2011) and miR-142 (Chapnik et al., 2014; Kramer et al., 2015; Sun et al., 2015) are often regulated by mRNA degradation. Interestingly, among miR-155 target genes, some are predominantly regulated by translation repression, some are mainly regulated by mRNA degradation, while the others are regulated by both mechanisms (Vigorito et al., 2007; Dorsett et al., 2008; Lu et al., 2009, 2014; O'Connell et al., 2009, 2010; Dudda et al., 2013; Escobar et al., 2014; Hu et al., 2014; Jin et al., 2015; Wang et al., 2015a), suggesting that different target genes of the same miRNA can be regulated through different mechanisms even in the same cell. It is a tempting possibility that cis-elements in mature miRNAs and target mRNAs determine the mechanism of miRNA action. Future investigation is warranted to identify these cis-elements, if they exist at all.


MicroRNA Mechanisms of Action: What have We Learned from Mice?

Jin HY, Xiao C - Front Genet (2015)

Contribution of translation repression and mRNA degradation to miRNA regulation of target gene expression in primary cells and tissues from miRNA mutant mice. Number in parentheses indicates the number of genes in each category. See also Table S1 for detailed information.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644800&req=5

Figure 1: Contribution of translation repression and mRNA degradation to miRNA regulation of target gene expression in primary cells and tissues from miRNA mutant mice. Number in parentheses indicates the number of genes in each category. See also Table S1 for detailed information.
Mentions: Here we sought to summarize the relative contribution of translation repression and mRNA degradation to miRNA regulation of functional targets in miRNA mutant mice. We focused on miRNA target genes whose protein and mRNA levels were measured concurrently in primary cells or tissues from mutant mice with genetic ablation or transgenic expression of individual miRNA genes. This includes a total of 159 target genes from 77 miRNA mutant mice (Table S1; Zhao et al., 2005, 2007; Lu et al., 2007, 2009, 2014; van Rooij et al., 2007; Vigorito et al., 2007; Dorsett et al., 2008; Liu et al., 2008, 2011, 2012, 2014; Wang et al., 2008, 2013a,b, 2014, 2015a,b; Boettger et al., 2009; Callis et al., 2009; O'Connell et al., 2009, 2010; Poy et al., 2009; Shan et al., 2009; Williams et al., 2009; Xin et al., 2009; Miyaki et al., 2010; Patrick et al., 2010; Yu et al., 2010; Biton et al., 2011; Boldin et al., 2011; Dunand-Sauthier et al., 2011; Jiang et al., 2011; Jordan et al., 2011; Ma et al., 2011, 2013; Nakamura et al., 2011; Sanuki et al., 2011; Shibata et al., 2011; Aurora et al., 2012; Callegari et al., 2012; Caruso et al., 2012; Dong et al., 2012; Gurha et al., 2012; Horie et al., 2012, 2013; Hsu et al., 2012; Liang et al., 2012, 2015; Mori et al., 2012; Tsai et al., 2012; Ucar et al., 2012; Wei et al., 2012, 2014; Zhuang et al., 2012; Belkaya et al., 2013; Bian et al., 2013; Danielson et al., 2013; Dorhoi et al., 2013; Dudda et al., 2013; Gebeshuber et al., 2013; Guo et al., 2013; Hasuwa et al., 2013; Heidersbach et al., 2013; Henao-Mejia et al., 2013; Khan et al., 2013; Mok et al., 2013; Song et al., 2013, 2014; Stadthagen et al., 2013; Tan et al., 2013; Wystub et al., 2013; Agudo et al., 2014; Ahmed et al., 2014; Burger et al., 2014; Chapnik et al., 2014; Dahan et al., 2014; Escobar et al., 2014; Giusti et al., 2014; Hu et al., 2014; Krzeszinski et al., 2014; Latreille et al., 2014; Pan et al., 2014; Stickel et al., 2014; Cushing et al., 2015; Jin et al., 2015; Kosaka et al., 2015; Kramer et al., 2015; Li et al., 2015a,b,c; Parchem et al., 2015; Sullivan et al., 2015; Sun et al., 2015; Tung et al., 2015; Xu et al., 2015; Yan et al., 2015; Zhang et al., 2015). Our analysis showed that 48% target genes are predominantly regulated by translation repression (76/159), 29% are regulated mainly by mRNA degradation (46/159), and 23% are regulated by both (37/159) (Figure 1). It is still unclear what determines the dominant mode of miRNA mechanism of action. As most of these studies measured target gene mRNA and protein levels under steady-state conditions, we speculate that differences in miRNA mechanism of action are not solely determined by the expression kinetics of miRNA or target mRNAs (Bazzini et al., 2012; Béthune et al., 2012; Djuranovic et al., 2012), but are instead attributed to cell type-, target mRNA-, or even miRNA-specific factors. Interestingly, almost all target genes identified in developing cells or tissues are mainly regulated by mRNA degradation, such as day 0 or day 2.5 cardiac cells (Heidersbach et al., 2013; Wei et al., 2014), embryonic stem cell-derived neurons (Tung et al., 2015), thymocytes (Belkaya et al., 2013; Henao-Mejia et al., 2013; Burger et al., 2014), bone marrow cells (Song et al., 2013), embryonic heart (Wystub et al., 2013; Liang et al., 2015), embryonic yolk sac (Wang et al., 2008), embryonic and neonatal epithelium (Ahmed et al., 2014), and fetal liver (Patrick et al., 2010). This is in sharp contrast to target genes identified in terminally differentiated cells, which are predominantly regulated by translation repression. It is conceivable that mRNA degradation gets rid of target gene mRNAs in a non-reversible way and provides an efficient way for cell fate determination, while translation repression is immediate, transient, and reversible, which is more suitable for differentiated cells to respond to environmental stresses. Our analysis also suggests miRNA-specific functional consequences. Several groups independently observed that target genes of miR-17~92 (Lu et al., 2007; Shan et al., 2009; Jiang et al., 2011; Bian et al., 2013; Danielson et al., 2013; Jin et al., 2015), miR-214 (Aurora et al., 2012; Wang et al., 2013b; Li et al., 2015b), miR-143/145 (Boettger et al., 2009; Jordan et al., 2011; Caruso et al., 2012; Dahan et al., 2014), and miR-146 (Boldin et al., 2011; Guo et al., 2013; Stickel et al., 2014) tend to be regulated at the translational level, but target genes of miR-122 (Hsu et al., 2012; Tsai et al., 2012), miR-140 (Miyaki et al., 2010; Nakamura et al., 2011) and miR-142 (Chapnik et al., 2014; Kramer et al., 2015; Sun et al., 2015) are often regulated by mRNA degradation. Interestingly, among miR-155 target genes, some are predominantly regulated by translation repression, some are mainly regulated by mRNA degradation, while the others are regulated by both mechanisms (Vigorito et al., 2007; Dorsett et al., 2008; Lu et al., 2009, 2014; O'Connell et al., 2009, 2010; Dudda et al., 2013; Escobar et al., 2014; Hu et al., 2014; Jin et al., 2015; Wang et al., 2015a), suggesting that different target genes of the same miRNA can be regulated through different mechanisms even in the same cell. It is a tempting possibility that cis-elements in mature miRNAs and target mRNAs determine the mechanism of miRNA action. Future investigation is warranted to identify these cis-elements, if they exist at all.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute La Jolla, CA, USA ; Kellogg School of Science and Technology, The Scripps Research Institute La Jolla, CA, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

A follow-up study employing temporal dissection of zebrafish development seems to reconcile these two opposite observations by revealing that translational repression precedes target mRNA decay, and suggesting that the immediate outcome of miRNA-target mRNA interaction is translation inhibition but mRNA degradation can follow (Bazzini et al., )... Similarly, re-analysis of the previous datasets from cultured cell lines transiently transfected with synthetic miRNA mimics also found that translation repression precedes mRNA degradation (Larsson and Nadon, )... However, the model miRNA used in the aforementioned zebrafish study, miR-430, is unique in that its expression is rapidly induced and reaches millions of copies per cell in a few hours after fertilization... As an extreme example, miR-122 is expressed at the estimated level of 5 × 10 copies per cell in hepatocytes (Chang et al., ; Jopling et al., )... This is still about 20 times lower than the million-copy-per-cell expression level of miR-430 in zebrafish embryos... It is conceivable that mRNA degradation gets rid of target gene mRNAs in a non-reversible way and provides an efficient way for cell fate determination, while translation repression is immediate, transient, and reversible, which is more suitable for differentiated cells to respond to environmental stresses... Several groups independently observed that target genes of miR-17~92 (Lu et al., ; Shan et al., ; Jiang et al., ; Bian et al., ; Danielson et al., ; Jin et al., ), miR-214 (Aurora et al., ; Wang et al., ; Li et al., ), miR-143/145 (Boettger et al., ; Jordan et al., ; Caruso et al., ; Dahan et al., ), and miR-146 (Boldin et al., ; Guo et al., ; Stickel et al., ) tend to be regulated at the translational level, but target genes of miR-122 (Hsu et al., ; Tsai et al., ), miR-140 (Miyaki et al., ; Nakamura et al., ) and miR-142 (Chapnik et al., ; Kramer et al., ; Sun et al., ) are often regulated by mRNA degradation... Interestingly, among miR-155 target genes, some are predominantly regulated by translation repression, some are mainly regulated by mRNA degradation, while the others are regulated by both mechanisms (Vigorito et al., ; Dorsett et al., ; Lu et al.,, ; O'Connell et al.,, ; Dudda et al., ; Escobar et al., ; Hu et al., ; Jin et al., ; Wang et al., ), suggesting that different target genes of the same miRNA can be regulated through different mechanisms even in the same cell... In the same vein, translatome analysis is more appropriate for measuring the global effect of a miRNA on its target genes, while transcriptome analysis often failed to identify any significant effect of miRNA deletion on its target genes, despite the obvious functional consequences in mutant mice (Matkovich et al., ; Boldin et al., ; Jiang et al., ; Agudo et al., ; Sullivan et al., ; Yuan et al., )... In the broader context of gene expression regulation, accumulating evidence shows that proteome and transcriptome are not sufficiently correlated to act as proxies for each other (Payne, ). miRNA-mediated translation regulation may play an important role in the de-coupling of translatome from transcriptome... We speculate that miRNAs emerged during evolution to increase the complexity of gene regulation, thereby contributing to the diversity of organisms.

No MeSH data available.