Abstract
It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability) under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability) is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits. A systematic exploration of these modules' parameter space reveals two classes of molecular switches, involving transitions in bistable (progression switches) or multistable (decision switches) regimes. We demonstrate the potential of decision switches for multifaceted stimulus processing, including strength, duration, and flexible discrimination. These tasks enhance response specificity, help to store short-term memories of recent signaling events, stabilize transient gene expression, and enable stochastic fate commitment. The relevance of these circuits is further supported by biological data, because we find them in numerous developmental scenarios. Indeed, many of the presented information-processing features of decision switches could ultimately demonstrate a more flexible control of epigenetic differentiation.
Highlights
The capability of cells to present different stable expression states while maintaining identical genetic content plays a significant role in differentiation, signal transduction and molecular decision-making
While multistable decision switches have been recently suggested as a rationale to explain co-expression of antagonistic master regulators in lineage specification scenarios [21,22], we show that these switches appear in mutual-inhibition architectures
Similar simplified models have been used to describe the coexistence of several expression states in specific cell fate systems, such as those involved in hematopoiesis [11,12,22] or embryonic stem cell differentiation [29]). We present this model as part of a general framework in relation to a broad number of biological scenarios, and fully characterize the type of information-processing features these circuits exhibit and their potential significance for a more flexible control of epigenetic differentiation
Summary
The capability of cells to present different stable expression states while maintaining identical genetic content plays a significant role in differentiation, signal transduction and molecular decision-making. The circuit should display some degree of nonlinearity, i.e., sigmoidality, on its constituent interactions [6,7,8] This sigmoidal behavior is typical of many molecular interactions and endows these genetic modules, interpreted as dynamical systems, with multistability, i.e., the possibility to find the system in alternative steady states under conditions in which all its biochemical parameters are fixed. Positive feedback loops at the core of more complex regulatory networks generally consists of simple structures controlling cell fate decisions This is normally associated to two complementary expression states, i.e., bistability (like the p42–Cdc system involved in Xenopus oocytes maturation [9], or the bacteriophage l genetic switch [10]), but three states is been recently discussed [11,12].
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