Gene autoregulation via intronic microRNAs and its functions

Abstract

BackgroundMicroRNAs, post-transcriptional repressors of gene expression, play a pivotal role in gene regulatory networks. They are involved in core cellular processes and their dysregulation is associated to a broad range of human diseases. This paper focus on a minimal microRNA-mediated regulatory circuit, in which a protein-coding gene (host gene) is targeted by a microRNA located inside one of its introns.ResultsAutoregulation via intronic microRNAs is widespread in the human regulatory network, as confirmed by our bioinformatic analysis, and can perform several regulatory tasks despite its simple topology. Our analysis, based on analytical calculations and simulations, indicates that this circuitry alters the dynamics of the host gene expression, can induce complex responses implementing adaptation and Weber’s law, and efficiently filters fluctuations propagating from the upstream network to the host gene. A fine-tuning of the circuit parameters can optimize each of these functions. Interestingly, they are all related to gene expression homeostasis, in agreement with the increasing evidence suggesting a role of microRNA regulation in conferring robustness to biological processes. In addition to model analysis, we present a list of bioinformatically predicted candidate circuits in human for future experimental tests.ConclusionsThe results presented here suggest a potentially relevant functional role for negative self-regulation via intronic microRNAs, in particular as a homeostatic control mechanism of gene expression. Moreover, the map of circuit functions in terms of experimentally measurable parameters, resulting from our analysis, can be a useful guideline for possible applications in synthetic biology.

The dual regulatory role of miR-204 in cancer

“…Interestingly, TRPM3 was validated to be a target of miR-204 [51], consistent with that some genes are autoregulated via intronic microRNAs [73]. Some stimuli may induce expression of both miR-204 and TRPM3 .…”

Modelling Competing Endogenous RNA Networks

“…Following [35], we consider two different settings: (i) to mimic a sudden signal which saturates ceRNA2 promoter at , the transcription rate of ceRNA2 switches from zero to a given value (), (ii) to mimic the opposite condition of a sudden drop of the activating signal at , the transcription rate of ceRNA2 switches from its initial value to zero ().…”

“…A recent work pointed out the function of incoherent miRNA-mediated feedforward loops (a transcription factor as master regulator of a miRNA and a target of both) in reducing noise from upstream regulators [43]. In [35] a minimal version of such motif (i.e. an intronic miRNA-mediated self regulation) has been mathematically analyzed.…”

TRPM3 and miR-204 Establish a Regulatory Circuit that Controls Oncogenic Autophagy in Clear Cell Renal Cell Carcinoma

“…This minimal regulatory circuit can be predicted by algorithms (Bosia et al, 2012), but there are few well-validated examples, such as miR-128b and ARPP-21 (Megrew et al, 2009) and miR-126 and EGFL7 (Sun et al, 2010, Nikolic et al, 2010). The discovery of the miR-204-TRPM3 relationship is particularly interesting as the expression of miR-204 results from VHL-stimulated generation of short transcripts that do not encode the full channel protein (Mikhaylova et al, 2012).…”