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Review
. 2009 Sep 8;1(9):762-70.
doi: 10.18632/aging.100085.

Coupling transcriptional and post-transcriptional miRNA regulation in the control of cell fate

Reut Shalgi  1 , Ran Brosh, Moshe Oren, Yitzhak Pilpel, Varda Rotter
Affiliations
Review

Coupling transcriptional and post-transcriptional miRNA regulation in the control of cell fate

Reut Shalgi et al. Aging (Albany NY). .

Abstract

miRNAs function as a critical regulatory layer in development, differentiation, and the maintenance of cell fate. Depletion of miRNAs from embryonic stem cells impairs their differentiation capacity. Total elimination of miRNAs leads to premature senescence in normal cells and tissues through activation of the DNA-damage checkpoint, whereas ablation of miRNAs in cancer cell lines results in an opposite effect, enhancing their tumorigenic potential. Here we compile evidence from the literature that point at miRNAs as key players in the maintenance of genomic integrity and proper cell fate. There is an apparent gap between our understanding of the subtle way by which miRNAs modulate protein levels, and their profound impact on cell fate. We propose that examining miRNAs in the context of the regulatory transcriptional and post-transcriptional networks they are embedded in may provide a broader view of their role in controlling cell fate.

Keywords: Dicer; cancer; genome integrity; miRNA; senescence.

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Conflict of interest statement

The authors declare no conflict of interests.

Figures

Figure 1.
Figure 1.. Proposed mechanisms for avoidance of regulation by miRNAs in cancer cells.
We propose that cancers may evolve to avoid regulation by miRNAs in order to enhance their tumorigenic potential. This might occur through a variety of mechanisms: (I) combined transcriptional/post-transcriptional FFL wiring, which may enhance the repression of several co-regulated miRNAs, thereby facilitating the expression of the mutual target genes; (II) global avoidance of miRNA regulation via expression of shorter 3' UTRs [42]; (III) global reduction in miRNA levels by impairing miRNA biogenesis in various ways, some of which were shown to happen in tumors, such as inhibition of Drosha processing [39,40] and pre-miRNA nuclear retention [36]. All of these are suggested as means that developing tumors may evolve to enhance proliferation and increase genome instability.
Figure 2.
Figure 2.. Different ways by which FFLs can account for the enhanced phenotypic effect of miRNAs on cell fate.
(A) miRNAs and TFs in FFLs tend to mutually target genes from the same pathway. (B) Additionally, co-regulated miRNAs and miRNA families co-target many genes in the same pathway, thus resulting in a significant total output, having a major effect on cell fate.
Figure 3.
Figure 3.. Possible roles for FFLs of miRNAs, Transcription Factors (TFs) and their mutual targets in facilitating spatiotemporal avoidance, or noise buffering.
miRNAs are often embedded in Feed-Forward loops (FFLs) with TFs, sharing mutual targets. It was shown that in many cases during development, miRNAs and their targets avoid expression in the same tissue or at the same developmental stage. This phenome-non was termed "miRNA-target spatiotemporal avoidance". The figure depicts how the network wiring of miRNAs in combined transcriptional/posttranscriptional FFLs may explain the spatio-temporal avoidance phenomenon. Different scenarios may facilitate spatial and temporal avoidance, where the TF and the miRNA are either negatively correlated in their expression across tissues (in A) or positively correlated, namely are expressed in the same tissue (B or C). (A) Spatial avoidance may be facilitated by the presented FFLs when expression of a miRNA and of a TF anti-correlates across tissues. (B) Temporal avoidance may be facilitated by the presented FFL when a miRNA and a TF are co-expressed in the same tissues, creating a temporal shut-down mechanism for their mutual targets, when there is a delay between the activation of the targets by the TF, and its activation of the miRNA. This delay may be achieved for example by a lower affinity binding site of the TF to the miRNA's promoter, by a natural miRNA processing time, etc. (C) Buffering of noise in expression may also be facilitated by a FFL wiring when a miRNA and a TF are co-expressed in the same tissues.
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