The Role Of Cis-Regulatory Modules In Genetic Regulatory Networks

Although some simple network modules give a good description of specific local regulatory circuits,it is important to understand how they function together as larger units to describe the responsive behavior of a whole organism.Previous studies on the simple network module typically only consider the case where the transcription factor regulate genes in an independent manner.However,in real gene regulatory networks,the signals received by cells are often processed in combination to generate specific gene responses,Moreover,from views of evolutionism,a cis-regulatory module,which processes information on input signals of the gene,is changeable,e.g.,cis-regulatory mutation,and such a mutation constitutes an important part of the genetic basis for adaptation.Therefore,studying the dynamics of gene regulatory networks with CRMs can lay a certain foundation for the design of biotechnology applications and the construction of biological networks.In this paper,we will consider the situation in which transcription factors regulate target genes in a logical combination,and study the dynamic behavior of two types of gene regulatory networks.One is a multicellular system of gene relaxation oscillators coupled through quorum sensing mechanisms,including eight different topologies,mainly analyze the influence of cis-regulatory modules on the system coupling type and clustering situation;the other is the interlinking positive and negative feedback loops,mainly study the influence of several biological factors on the interlinking positive and negative feedback loop systems with CRMs.The main contents are as follows:(1)First,the mathematical model of the relaxation oscillator multi-cell system is established.Then,the Kuramoto phase reduction method is used to determine the coupling type of the system,and the phase synchronization characteristics of the two coupled oscillators are analyzed;the Okuda balance clustering stability criterion is used to determine the balance clustering mode of the multi-cell system,and the corre-sponding time series diagram is displayed.The results show that complete synchronization only occurs in the case of attractive coupling,while repulsive coupling only leads to the occurrence of balance clustering.In addition,in the study of the AND logic operation of model 2,we have found more abundant balance clustering states than before,and there are as many as 18 types of stable balance clustering states.Both the-oretical analysis and numerical simulation show that,different CRMs will drive fundamentally different cell patterns,including complete synchronization,various balance clustering states and non-balance clustering states.Cellular patterning formation is a hallmark of coordinated cell behavior in single and multicellular organisms.Our research reveals the mechanism of cell pattern formation,enriching our understanding and knowledge of cell phenomena.(2)Model the interlinking positive and negative feedback loops,and consider the role of the cis-regulatory module with ANDN logic operations.Taking the parameter u_xthat regulates the concentration of protein X in the cis-regulatory input function as the bifurcation parameter,changing one of the positive feedback strength and the negative feedback strength,the result shows that the positive feedback strength u_yregulates the size of the bistability region of the system,and the increase of the negative feedback strength u_zbreaks the flexibility of bistability system switching.Next,consider the impact of the fast and slow time scale on the system,the interesting dynamic phenomenon of excitability first appeared,and its existence greatly enriches the dynamics of the system;then it is found that enhancing the positive feedback strength u_ycan tune the system from excitability to bistability;enhancing the negative feedback strength u_zwill leads to several typical bifurcation structures in the system:when uz is appropriately small,the system transitions from excitable state to oscillation states,when u_zis increased,the excitable state of the system disappears,oscillation states and monostable states can appear;when u_zis large enough,the system only exhibits monostable state.Finally,consider the influence of the signal on the ANDN system with fast and slow time scales.Taking the signal strength S as the bifurcation parameter,when considering the influence of the strength of the positive feedback,the dynamic behavior of this system can switch between monostable,bistable,excitable and oscillation;and increasing the strength of negative feedback will reverse the effect of increasing the strength of positive feedback.In addition,We also show the distribution area of various dynamic phenomena in the two-parameter distribution diagram.The results show that by adjusting the magnitude of the feedback intensity,the IPNFLs system with CRMs can be designed into a more flexible module that performs multiple functions without changing the system topology.These results will help us to summarize the design principles of biological networks.In the above model,we use MATLAB to realize the numerical simulation of the Kuramoto phase reduction method and the Okuda equilibrium clustering stability criterion,and use XPPAUT to draw the bifurcation diagram and the two-parameter distribution diagram.Finally,summarize the results of the full text research,and put forward some questions worthy of further in-depth study.