A novel feedback loop that controls bimodal expression of genetic competence

Gene expression can be highly heterogeneous in clonal cell populations. An extreme type of heterogeneity is the so-called bistable or bimodal expression, whereby a cell can differentiate into two alternative expression states, and consequently a population will be composed of cells that are ‘ON’ and cells that are ‘OFF’. Stochastic fluctuations of protein levels, also referred to as noise, provide the necessary source of heterogeneity that must be amplified by autostimulatory feedback regulation to obtain the bimodal response. A classical model of bistable differentiation is the development of genetic competence in Bacillus subtilis. Noise in expression of the transcription factor ComK ultimately determines the fraction of cells that enter the competent state. Due to its intrinsic random nature, noise is difficult to investigate. We adapted an artificial autostimulatory loop that bypasses all known ComK regulators, to screen for possible factors that affect noise in the bimodal regulation of ComK. This led to the discovery of Kre, a novel factor that controls the bimodal expression of ComK. Kre appears to affect the stability of comK mRNA. Interestingly, ComK itself represses the expression of kre, adding a new double negative feedback loop to the intricate ComK regulation circuit. Our data emphasize that mRNA stability is an important factor in bimodal regulation. Comparing wild type Bacillus subtilis strain 168 (n=2) with Bacillus subtilis PG479 (Δkre, n = 3).