MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems

Abstract

Biological systems are continuously challenged by an environment that is variable. Yet, a key feature of developmental and physiological processes is their remarkable stability. This review considers how microRNAs contribute to gene regulatory networks that confer robustness.

Figure 1.

miRNAs involved in feedback motifs. (A) Simple positive and negative feedback loops. (B) miR-9a in a positive feedback loop in SOP specification in Drosophila. The boxes represent cells within the proneural cluster. In the blue cell, the Senseless–proneural gene positive feedback circuit dominates and leads to SOP differentiation. Senseless activates Delta, increasing Notch activity in adjacent cells. Notch inhibits proneural genes, allowing miR-9a repression of Senseless to dominate in these cells. (C) lsy-6 and miR-273 in a negative feedback loop controlling left/right asymmetry in ASE neurons of C. elegans. The transcription factors encoded by cog-1 and die-1 are active in ASER and ASEL, respectively. cog-1 activates miR-273 miRNAs, which repress die-1 in ASER. die-1 activates lsy-6, which represses cog-1 in ASEL. This initial asymmetry is stabilized by positive autoregulation of cog-1 in ASER. (D) miR-14 acts in a negative feedback loop modulating EcR activity. EcR positively autoregulates. miR-14 limits EcR levels, which in turn negatively regulates miR-14. (E) miR-124 in a negative feedback loop in the mouse cortex. The open boxes represent cells. Ephrin-B1 activity represses miR-124 in neural progenitors. miR-124 inhibits Ephrin-B1 and induces neuronal differentiation. (F) miR-375 acts in a negative feedback regulating insulin secretion. High glucose levels inhibit miR-375. miR-375 inhibits myotrophin and Pdpk-1, reducing insulin secretion. Circulating glucose promotes insulin secretion directly, and indirectly represses miR-375.

Figure 2.

miRNAs involved in feedforward motifs. (A) Feedforward motifs where X regulates Z directly and indirectly through regulation of Y. Coherent motifs have the direct and indirect paths from X acting on the target Z in the same direction. Incoherent motifs have opposite signs for the two paths. (B) miR-7 acts in two coherent feedforward motifs. Yan is a miR-7 target. In one motif (gray), Yan represses miR-7 directly and indirectly. In the indirect arm, Yan represses Phyllopod, alleviating repression of Ttk-69, which represses miR-7. In the second motif (red), Pnt-P1 directly activates miR-7, which represses Yan. Pnt-P1 represses yan directly. (C) let-7 acts in a coherent feedforward motif (gray), modulating oncogenic transformation. NF-κB induces IL6 expression directly. In the indirect arm, NF-κB activity inhibits let-7, alleviating repression of IL6. let-7 prevents noise in the activity of NF-κB or IL6 from triggering the positive feedback loop (red). (D) miR-7 acts in an incoherent feedforward motif. Atonal activates E(spl) directly. Atonal also represses E(spl) via miR-7. Atonal activity results in a pulse of E(spl) followed by a lower level of steady-state expression due to Atonal-induced miR-7 activity. (E) miR-20 and miR-17-5p act in an incoherent feedforward motif. c-Myc activates E2F directly. c-Myc also represses E2F via miR-17-5p and miR-20. c-Myc activity results in a pulse of E2F to promote cell cycle progression.