53 research outputs found
Gene autoregulation via intronic microRNAs and its functions
Background: MicroRNAs, 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. Results: Autoregulation 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. Conclusions: The
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.Comment: 29 pages and 7 figures in the main text, 18 pages of Supporting
Informatio
A combination of transcriptional and microRNA regulation improves the stability of the relative concentrations of target genes
It is well known that, under suitable conditions, microRNAs are able to fine
tune the relative concentration of their targets to any desired value. We show
that this function is particularly effective when one of the targets is a
Transcription Factor (TF) which regulates the other targets. This combination
defines a new class of feed-forward loops (FFLs) in which the microRNA plays
the role of master regulator. Using both deterministic and stochastic equations
we show that these FFLs are indeed able not only to fine-tune the TF/target
ratio to any desired value as a function of the miRNA concentration but also,
thanks to the peculiar topology of the circuit, to ensures the stability of
this ratio against stochastic fluctuations. These two effects are due to the
interplay between the direct transcriptional regulation and the indirect
TF/Target interaction due to competition of TF and target for miRNA binding
(the so called "sponge effect"). We then perform a genome wide search of these
FFLs in the human regulatory network and show that they are characterizedby a
very peculiar enrichment pattern. In particular they are strongly enriched in
all the situations in which the TF and its target have to be precisely kept at
the same concentration notwithstanding the environmental noise. As an example
we discuss the FFL involving E2F1 as Transcription Factor, RB1 as target and
miR-17 family as master regulator. These FFLs ensure a tight control of the
E2F/RB ratio which in turns ensures the stability of the transition from the
G0/G1 to the S phase in quiescent cells.Comment: 23 pages, 10 figure
On the role of extrinsic noise in microRNA-mediated bimodal gene expression
Several studies highlighted the relevance of extrinsic noise in shaping cell decision making and differentiation in molecular networks. Bimodal distributions of gene expression levels provide experimental evidence of phenotypic differentiation, where the modes of the distribution often correspond to different physiological states of the system. We theoretically address the presence of bimodal phenotypes in the context of microRNA (miRNA)-mediated regulation. MiRNAs are small noncoding RNA molecules that downregulate the expression of their target mRNAs. The nature of this interaction is titrative and induces a threshold effect: below a given target transcription rate almost no mRNAs are free and available for translation. We investigate the effect of extrinsic noise on the system by introducing a fluctuating miRNA-transcription rate. We find that the presence of extrinsic noise favours the presence of bimodal target distributions which can be observed for a wider range of parameters compared to the case with intrinsic noise only and for lower miRNA-target interaction strength. Our results suggest that combining threshold-inducing interactions with extrinsic noise provides a simple and robust mechanism for obtaining bimodal populations without requiring fine tuning. Furthermore, we characterise the protein distribution’s dependence on protein half-life
Stochastic sequestration dynamics: A minimal model with extrinsic noise for bimodal distributions and competitors correlation
Many biological processes are known to be based on molecular sequestration. This kind of dynamics involves two types of molecular species, namely targets and sequestrants, that bind to form a complex. In the simple framework of mass-action law, key features of these systems appear to be threshold-like profiles of the amounts of free molecules as a function of the parameters determining their possible maximum abundance. However, biochemical processes are probabilistic and take place in stochastically fluctuating environments. How these different sources of noise affect the final outcome of the network is not completely characterised yet. In this paper we specifically investigate the effects induced by a source of extrinsic noise onto a minimal stochastic model of molecular sequestration. We analytically show how bimodal distributions of the targets can appear and characterise them as a result of noise filtering mediated by the threshold response. We then address the correlations between target species induced by the sequestrant and discuss how extrinsic noise can turn the negative correlation caused by competition into a positive one. Finally, we consider the more complex scenario of competitive inhibition for enzymatic kinetics and discuss the relevance of our findings with respect to applications
Distinct retrograde microtubule motor sets drive early and late endosome transport
Although subcellular positioning of endosomes significantly impacts on their functions, the molecular
mechanisms governing the different steady-state distribution of early endosomes (EEs) and late
endosomes (LEs)/lysosomes (LYs) in peripheral and perinuclear eukaryotic cell areas, respectively,
are still unsolved. We unveil that such differences arise because, while LE retrograde transport
depends on the dynein microtubule (MT) motor only, the one of EEs requires the cooperative
antagonism of dynein and kinesin-14 KIFC1, a MT minus end-directed motor involved in cancer
progression. Mechanistically, the Ser-x-Ile-Pro (SxIP) motif-mediated interaction of the endoplasmic
reticulum transmembrane protein stromal interaction molecule 1 (STIM1) with the MT plus end
binding protein 1 (EB1) promotes its association with the p150Glued subunit of the dynein activator
complex dynactin and the distinct location of EEs and LEs/LYs. The peripheral distribution of EEs
requires their p150Glued-mediated simultaneous engagement with dynein and SxIP motif-containing
KIFC1, via HOOK1 and HOOK3 adaptors, respectively. In sum, we provide evidence that distinct
minus end directed MT motor systems drive the differential transport and subcellular distribution of
EEs and LEs in mammalian cells
RNAs competing for microRNAs mutually influence their fluctuations in a highly non-linear microRNA-dependent manner in single cells
We used an experimental design based on two bidirectional plasmids and flow cytometry measurements of cotransfected mammalian cells. We validated a stochastic gene interaction model that describes how mRNAs can influence each other’s fluctuations in a miRNA-dependent manner in single cells. We show that miRNA–target correlations eventually lead to either bimodal cell population distributions with high and low target expression states, or correlated fluctuations across targets when the pool of unbound targets and miRNAs are in near-equimolar concentration. We found that there is an optimal range of conditions for the onset of cross-regulation, which is compatible with 10–1000 copies of targets per cell
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