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What do all the (human) micro-RNAs do?

Ultsch A, Lötsch J - BMC Genomics (2014)

Bottom Line: The present analysis transferred this knowledge to a systems-biology level.A comprehensible and precise description of the biological processes in which the genes that are influenced by miRNAs are notably involved could be made.The analysis also suggests that miRNAs especially control the expression of genes that control the expression of genes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Pharmacology, Goethe - University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. j.loetsch@em.uni-frankfurt.de.

ABSTRACT

Background: Micro-RNAs (miRNA) are attributed to the systems biological role of a regulatory mechanism of the expression of protein coding genes. Research has identified miRNAs dysregulations in several but distinct pathophysiological processes, which hints at distinct systems-biology functions of miRNAs. The present analysis approached the role of miRNAs from a genomics perspective and assessed the biological roles of 2954 genes and 788 human miRNAs, which can be considered to interact, based on empirical evidence and computational predictions of miRNA versus gene interactions.

Results: From a genomics perspective, the biological processes in which the genes that are influenced by miRNAs are involved comprise of six major topics comprising biological regulation, cellular metabolism, information processing, development, gene expression and tissue homeostasis. The usage of this knowledge as a guidance for further research is sketched for two genetically defined functional areas: cell death and gene expression. Results suggest that the latter points to a fundamental role of miRNAs consisting of hyper-regulation of gene expression, i.e., the control of the expression of such genes which control specifically the expression of genes.

Conclusions: Laboratory research identified contributions of miRNA regulation to several distinct biological processes. The present analysis transferred this knowledge to a systems-biology level. A comprehensible and precise description of the biological processes in which the genes that are influenced by miRNAs are notably involved could be made. This knowledge can be employed to guide future research concerning the biological role of miRNA (dys-) regulations. The analysis also suggests that miRNAs especially control the expression of genes that control the expression of genes.

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Related in: MedlinePlus

Proposed “hyper-regulation” of gene expression by miRNAs. The figure shows the role of miRNAs in the complex transcriptional network (blue arrow). By regulating (blue arrow) the expression of genes that are involved in the regulation of the expression of genes, a miRNA-dependent regulatory mechanism of gene regulation is formed on top of the miRNA-independent regulation of gene expression (green arrow). By this regulatory mechanism, proposed as “hyper-regulation” of gene expression (blue arrow), miRNAs interfere with the whole transcriptome mainly including intranuclear mechanisms besides the well-known extranuclear (red arrow) mechanisms. Hyper-regulation accommodates observations of global gene down-regulation in the absence of miRNAs [47] which downregulate gene product that reduce gene transcription such as DNA methyltransferases (Additional file 2: Table S1. RegulatedGenes_vs_miRNAs_Matrix.xlsx).
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Fig5: Proposed “hyper-regulation” of gene expression by miRNAs. The figure shows the role of miRNAs in the complex transcriptional network (blue arrow). By regulating (blue arrow) the expression of genes that are involved in the regulation of the expression of genes, a miRNA-dependent regulatory mechanism of gene regulation is formed on top of the miRNA-independent regulation of gene expression (green arrow). By this regulatory mechanism, proposed as “hyper-regulation” of gene expression (blue arrow), miRNAs interfere with the whole transcriptome mainly including intranuclear mechanisms besides the well-known extranuclear (red arrow) mechanisms. Hyper-regulation accommodates observations of global gene down-regulation in the absence of miRNAs [47] which downregulate gene product that reduce gene transcription such as DNA methyltransferases (Additional file 2: Table S1. RegulatedGenes_vs_miRNAs_Matrix.xlsx).

Mentions: Thus, miRNA control applies in particular to the expression of genes that control the expression of genes, which we propose as “hyper-regulation” (Figure 5). The accepted role of miRNAs is the steering (inhibition) of the abundance of gene products, which is mechanistically exerting its functional infraction mainly in the cytoplasm. Hyper-regulation adds to mechanisms of gene expression control. It points at so far unappreciated increased complexity of gene expression control exceeding current paradigms. It can be hypothesized that miRNA mediated control represents an ancient major mechanism of cellular control providing small versatile molecules at comparably less metabolic effort for respective synthesis compared to protein translation. These systems are being found at all levels of gene expression from transcriptional fine-tuning. This was shown for the transcription activator Ets-1 where variable phosphorylation serves to fine-tune transcription at the level of DNA binding [44], the increasingly populated system of non-protein-coding regulatory RNAs increasing the diversity of control of genome dynamics and developmental programming [45], and the tight control of p53 as “guardian of the genome” shown to be closely regulated by miR-34a [46]. When considering that regulatory mechanisms may also repress genes that repress gene expression, such as all three DNA methyltransferases (DNMT 1, 3a and 3b; Additional file 2: Table S1. RegulatedGenes_vs_miRNAs_Matrix.xlsx), present findings also accommodate observations of genes being down-regulated following the deletion of dicer and thus abolishing the presence of miRNAs [47].Figure 5


What do all the (human) micro-RNAs do?

Ultsch A, Lötsch J - BMC Genomics (2014)

Proposed “hyper-regulation” of gene expression by miRNAs. The figure shows the role of miRNAs in the complex transcriptional network (blue arrow). By regulating (blue arrow) the expression of genes that are involved in the regulation of the expression of genes, a miRNA-dependent regulatory mechanism of gene regulation is formed on top of the miRNA-independent regulation of gene expression (green arrow). By this regulatory mechanism, proposed as “hyper-regulation” of gene expression (blue arrow), miRNAs interfere with the whole transcriptome mainly including intranuclear mechanisms besides the well-known extranuclear (red arrow) mechanisms. Hyper-regulation accommodates observations of global gene down-regulation in the absence of miRNAs [47] which downregulate gene product that reduce gene transcription such as DNA methyltransferases (Additional file 2: Table S1. RegulatedGenes_vs_miRNAs_Matrix.xlsx).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289375&req=5

Fig5: Proposed “hyper-regulation” of gene expression by miRNAs. The figure shows the role of miRNAs in the complex transcriptional network (blue arrow). By regulating (blue arrow) the expression of genes that are involved in the regulation of the expression of genes, a miRNA-dependent regulatory mechanism of gene regulation is formed on top of the miRNA-independent regulation of gene expression (green arrow). By this regulatory mechanism, proposed as “hyper-regulation” of gene expression (blue arrow), miRNAs interfere with the whole transcriptome mainly including intranuclear mechanisms besides the well-known extranuclear (red arrow) mechanisms. Hyper-regulation accommodates observations of global gene down-regulation in the absence of miRNAs [47] which downregulate gene product that reduce gene transcription such as DNA methyltransferases (Additional file 2: Table S1. RegulatedGenes_vs_miRNAs_Matrix.xlsx).
Mentions: Thus, miRNA control applies in particular to the expression of genes that control the expression of genes, which we propose as “hyper-regulation” (Figure 5). The accepted role of miRNAs is the steering (inhibition) of the abundance of gene products, which is mechanistically exerting its functional infraction mainly in the cytoplasm. Hyper-regulation adds to mechanisms of gene expression control. It points at so far unappreciated increased complexity of gene expression control exceeding current paradigms. It can be hypothesized that miRNA mediated control represents an ancient major mechanism of cellular control providing small versatile molecules at comparably less metabolic effort for respective synthesis compared to protein translation. These systems are being found at all levels of gene expression from transcriptional fine-tuning. This was shown for the transcription activator Ets-1 where variable phosphorylation serves to fine-tune transcription at the level of DNA binding [44], the increasingly populated system of non-protein-coding regulatory RNAs increasing the diversity of control of genome dynamics and developmental programming [45], and the tight control of p53 as “guardian of the genome” shown to be closely regulated by miR-34a [46]. When considering that regulatory mechanisms may also repress genes that repress gene expression, such as all three DNA methyltransferases (DNMT 1, 3a and 3b; Additional file 2: Table S1. RegulatedGenes_vs_miRNAs_Matrix.xlsx), present findings also accommodate observations of genes being down-regulated following the deletion of dicer and thus abolishing the presence of miRNAs [47].Figure 5

Bottom Line: The present analysis transferred this knowledge to a systems-biology level.A comprehensible and precise description of the biological processes in which the genes that are influenced by miRNAs are notably involved could be made.The analysis also suggests that miRNAs especially control the expression of genes that control the expression of genes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Pharmacology, Goethe - University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. j.loetsch@em.uni-frankfurt.de.

ABSTRACT

Background: Micro-RNAs (miRNA) are attributed to the systems biological role of a regulatory mechanism of the expression of protein coding genes. Research has identified miRNAs dysregulations in several but distinct pathophysiological processes, which hints at distinct systems-biology functions of miRNAs. The present analysis approached the role of miRNAs from a genomics perspective and assessed the biological roles of 2954 genes and 788 human miRNAs, which can be considered to interact, based on empirical evidence and computational predictions of miRNA versus gene interactions.

Results: From a genomics perspective, the biological processes in which the genes that are influenced by miRNAs are involved comprise of six major topics comprising biological regulation, cellular metabolism, information processing, development, gene expression and tissue homeostasis. The usage of this knowledge as a guidance for further research is sketched for two genetically defined functional areas: cell death and gene expression. Results suggest that the latter points to a fundamental role of miRNAs consisting of hyper-regulation of gene expression, i.e., the control of the expression of such genes which control specifically the expression of genes.

Conclusions: Laboratory research identified contributions of miRNA regulation to several distinct biological processes. The present analysis transferred this knowledge to a systems-biology level. A comprehensible and precise description of the biological processes in which the genes that are influenced by miRNAs are notably involved could be made. This knowledge can be employed to guide future research concerning the biological role of miRNA (dys-) regulations. The analysis also suggests that miRNAs especially control the expression of genes that control the expression of genes.

Show MeSH
Related in: MedlinePlus