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Abstract: We study the functional characteristics of a two-gene motif consisting of adouble positive feedback loop and an autoregulatory negative feedback loop.
Themotif appears in the gene regulatory network controlling the functionalactivity of pancreatic $\beta$-cells.
The model exhibits bistability andhysteresis in appropriate parameter regions.
The two stable steady statescorrespond to low OFF state and high ON state protein levels respectively.Using a deterministic approach, we show that the region of bistabilityincreases in extent when the copy number of one of the genes is reduced fromtwo to one.
The negative feedback loop has the effect of reducing the size ofthe bistable region.
Loss of a gene copy, brought about by mutations, hampersthe normal functioning of the $\beta$-cells giving rise to the geneticdisorder, maturity-onset diabetes of the young MODY.
The diabetic phenotypemakes its appearance when a sizable fraction of the $\beta$-cells is in the OFFstate.
Using stochastic simulation techniques, we show that, on reduction ofthe gene copy number, there is a transition from the monostable ON to the ONstate in the bistable region of the parameter space.
Fluctuations in theprotein levels, arising due to the stochastic nature of gene expression, cangive rise to transitions between the ON and OFF states.
We show that as thestrength of autorepression increases, the ON$\to$OFF state transitions becomeless probable whereas the reverse transitions are more probable.
Theimplications of the results in the context of the occurrence of MODY arepointed out





Author: Subhasis Banerjee, Indrani Bose

Source: https://arxiv.org/



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