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Functional characteristics of a double positive feedback loop coupled with autorepression. | LitMetric

AI Article Synopsis

  • The study focuses on a two-gene motif with both positive and negative feedback loops that regulate pancreatic beta-cell function, showing its involvement in the genetic disorder MODY.
  • The model demonstrates bistability, meaning the system can exist in two stable protein levels (low OFF state and high ON state), and finds that reducing the copy number of one gene expands the bistable region.
  • Stochastic simulations reveal that fluctuations in protein levels can cause transitions between ON and OFF states, and increased autorepression makes transitioning from ON to OFF less likely while enhancing the reverse.

Article Abstract

We study the functional characteristics of a two-gene motif consisting of a double positive feedback loop and an autoregulatory negative feedback loop. The motif appears in the gene regulatory network controlling the functional activity of pancreatic beta-cells. The model exhibits bistability and hysteresis in appropriate parameter regions. The two stable steady states correspond to low (OFF state) and high (ON state) protein levels, respectively. Using a deterministic approach, we show that the region of bistability increases in extent when the copy number of one of the genes is reduced from 2 to 1. The negative feedback loop has the effect of reducing the size of the bistable region. Loss of a gene copy, brought about by mutations, hampers the normal functioning of the beta-cells giving rise to the genetic disorder, maturity-onset diabetes of the young (MODY). The diabetic phenotype makes its appearance when a sizable fraction of the beta-cells is in the OFF state. Using stochastic simulation techniques we show that, on reduction of the gene copy number, there is a transition from the monostable ON to the ON state in the bistable region of the parameter space. Fluctuations in the protein levels, arising due to the stochastic nature of gene expression, can give rise to transitions between the ON and OFF states. We show that as the strength of autorepression increases, the ON --> OFF state transitions become less probable whereas the reverse transitions are more probable. The implications of the results in the context of the occurrence of MODY are pointed out.

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Source
http://dx.doi.org/10.1088/1478-3975/5/4/046008DOI Listing

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