Sriram K, Soliman Sylvain, Fages François
Project-team Contraintes, INRIA Paris-Rocquencourt, France.
J Theor Biol. 2009 May 7;258(1):71-88. doi: 10.1016/j.jtbi.2009.01.008. Epub 2009 Jan 24.
The two element mutual activation and inhibitory positive feedback loops are a common motifs that occur in many biological systems in both isolated and interlocked form, as for example, in the cell division cycle and thymus differentiation in eukaryotes. The properties of three element interlocked positive feedback loops that embeds both mutual activation and inhibition are studied in depth for their bistable properties by performing bifurcation and stochastic simulations. Codimension one and two bifurcations reveal important properties like robustness to parameter variations and adaptability under various conditions by its ability to fine tune the threshold to a wide range of values and to maintain a wide bistable regime. Furthermore, we show that in the interlocked circuit, mutual inhibition controls the decision to switch from OFF to ON state, while mutual activation enforces the decision. This view is supported through a concrete biological example Candida albicans, a human fungal pathogen that can exist in two distinctive cell types; one in the default white state and the other in an opaque form. Stochastic switching between these two forms takes place due to the epigenetic alternation induced by the transcriptional regulators in the circuit, albeit without any rearrangement of the nuclear chromosomes. The transcriptional regulators constitute interlocked mutual activation and inhibition feedback circuits that provide adaptable threshold and wide bistable regime. These positive feedback loops are shown to be responsible for robust noise induced transitions without chattering, persistence of particular phenotypes for many generations and selective exhibition of one particular form of phenotype when mutated. Finally, we propose for synthetic biology constructs to use interlocked positive feedback loops instead of two element positive feedback loops because they are better controlled than isolated mutual activation and mutual inhibition feedback circuits.
双元件相互激活和抑制性正反馈回路是一种常见基序,以孤立或连锁形式出现在许多生物系统中,例如真核生物的细胞分裂周期和胸腺分化。通过进行分岔和随机模拟,深入研究了嵌入相互激活和抑制的三元件连锁正反馈回路的双稳态特性。一维和二维分岔揭示了重要特性,如对参数变化的鲁棒性以及在各种条件下的适应性,因为它能够将阈值微调至广泛的值范围并维持广泛的双稳态区域。此外,我们表明在连锁回路中,相互抑制控制从关闭状态切换到开启状态的决策,而相互激活则强化该决策。通过一个具体的生物学例子——白色念珠菌(一种可存在于两种不同细胞类型的人类真菌病原体,一种处于默认的白色状态,另一种处于不透明形式)支持了这一观点。这两种形式之间的随机切换是由于回路中转录调节因子诱导的表观遗传变化而发生的,尽管没有任何核染色体的重排。转录调节因子构成连锁的相互激活和抑制反馈回路,提供适应性阈值和广泛的双稳态区域。这些正反馈回路被证明负责稳健的噪声诱导转变而无颤动、特定表型多代持续存在以及突变时一种特定表型形式的选择性展现。最后,我们建议合成生物学构建体使用连锁正反馈回路而非双元件正反馈回路,因为它们比孤立的相互激活和相互抑制反馈回路更易于控制。