Roles for microRNAs in conferring robustness to biological processes

Abstract

Biological systems use a variety of mechanisms to maintain their functions in the face of environmental and genetic perturbations. Increasing evidence suggests that, among their roles as posttranscriptional repressors of gene expression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcing transcriptional programs and attenuating aberrant transcripts, and they may in some network contexts help suppress random fluctuations in transcript copy number. These activities have important consequences for normal development and physiology, disease, and evolution. Here, we will discuss examples and principles of miRNAs that contribute to robustness in animal systems.

Figure 1

Anticorrelated expression of miRNAs and targets in developmental transitions. In the Drosophila embryo, neurectodermal progenitors express miR-124 as they differentiate into neurons. Neuronal genes that are induced during this transition tend not to have miR-124 sites, whereas genes expressed in epidermal tissues that are also ectodermal derivatives are enriched for miR-124 sites (Stark et al., 2005). Thus, expression of miR-124 stabilizes the neuronal transition. A reciprocal pattern holds for the ectoderm-specific miR-9a.

Figure 2

Network motifs for cell fate switches. (A) A coherent feedforward loop both directly and indirectly inhibits the cell cycle regulator E2F1 in granulopoiesis. (B) A mutual negative feedback loop contributes to bistability between myeloid precursors and granulocytes. (C) A positive feedback loop enforces lineage commitment of nematode “2 degrees” vulval cells.

Figure 3

Positive feedback can amplify small changes. A transient inflammatory cue induces stable malignant transformation through an NF-κB/IL6 positive feedback network that is normally kept in check by let-7. Diagram adapted from (Iliopoulos et al., 2009).

Figure 4

miRNAs can reduce noise in gene expression. (A) A negative feedback loop contributes to homeostasis for MeCP2 protein in neurons. (B) Post-transcriptional repression to attenuate transcriptional noise. Two transcription-translation strategies to synthesize the same mean level of a protein, here 20 molecules per cell per unit of time. Strong transcription corresponds to more frequent mRNA bursts (black bars). Translation amplifies mRNA bursts into protein bursts (purple bars) so a more consistent protein output occurs when each mRNA produces fewer molecules of protein. (C) Uncoupling of target protein output from mRNA input (left) by means of an incoherent feedforward loop (right) in which miRNA and target mRNA are transcriptionally co-induced. Cartooned from (Bleris et al., 2011) data.

Figure 5

miRNA-target interaction produces non-linear target protein output. Below a certain threshold of target mRNA production, the target is strongly repressed (pink). Above the threshold, repression is weaker and the target can exert competitive “sponge”-like effects (blue). The position of the threshold depends on miRNA concentration. Cartooned from (Mukherji et al., 2011) data.