Coherent Feed Forward Loops

Transcription

1 Coherent Feed Forward Loops Dr. M. Vijayalakshmi School of Chemical and Biotechnology SASTRA University Joint Initiative of IITs and IISc Funded by MHRD Page 1 of 10

2 Table of Contents 1 INTRODUCTION COHERENT FEED FORWARD LOOP TYPE I (CFFL I) COHERENT FEED FORWARD LOOP TYPE II (CFFL II) COHERENT FEED FORWARD LOOP TYPE III (CFFL III) COHERENT FEED FORWARD LOOP TYPE IV (CFFL IV) REFERENCES TEXT BOOK LITERATURE REFERENCES Joint Initiative of IITs and IISc Funded by MHRD Page 2 of 10

3 1 Introduction Let us revisit the concepts of network motifs, we discussed in the last class. We recollect that the Feed Forward Loop is a network motif constituted by a transcription factor X which regulates another transcription factor Y and both X and Y regulate a gene Z. Such Feed Forward Loops comprise two parallel paths that regulate the circuit, a direct path from X->Z and an indirect path of X->Z through Y. A Coherent Feed Forward Loop has the same overall sign for the indirect path as that of the direct path of regulation. Though all the Feed Forward Loops appear with equal frequency across transcription networks, Type -1 Coherent FFL is the most abundant type of FFL and shows a positive sign for all the regulations involved in the circuit. In order to explain the functional logic exhibited by the Feed Forward Loop, let us consider a typical situation inside a cell during the process of transcription. Let the cell express multiple copies of a protein X, one of the transcription factors in the Feed Forward Loop. Let signal S x be the input to X. This X is inactive without the signal S x. At a time t=0, the strong signal S x triggers the activation of X, transiting it to a form X *. This process is called a step like stimulation of X. X *, the active protein now binds to the promoter of gene Y initiates production of protein Y, the second transcription factor in the Feed Forward Loop. Mean while X * binds to the promoter of gene Z. If the circuit follows an AND logic (input function at the Z promoter), X * alone cannot activate the production of Z. it requires the binding of both X * and Y *. This indicates that Y should build up to sufficient levels of expression to cross the activation threshold of gene Z (K YZ ).Activation of Z also requires the presence of S y which activates Y to its form Y *. Therefore the appearance of the signal S x and Y are both required to activate Z. This introduces a delay in the production of Z. This function is represented by the truth tables below. Joint Initiative of IITs and IISc Funded by MHRD Page 3 of 10

4 1.1 Coherent Feed Forward Loop type I (CFFL I) Fig 1 (a) Coherent Feed Forward Loop Type I (CFFL I) Table 1 (a) AND- and OR- gates at the Z promoter for CFFL I Case 1: Steady State In an AND logic circuit, described in Fig 1 (a) when both the signals S X and S Y are present. In the presence of signals the system reaches a steady state. The active part of transcription factor X which is X* binds to the promoter gene Z through gene Y and X binds to Z independent of Y. So gene Z receives two inputs (one from gene X and the other from Y) leading to the expression of both the genes. In short, X controls Z, forming a direct pathway. X controls Z, through Y forming an indirect pathway. Case 2: S X ON state Let us now consider the case when S X is ON. In the AND circuit, When S X is on, the transcription factor of the protein X becomes active X*and binds to the promoter of gene Z, thus expressing Z. (direct path). The activated protein X* also binds to promoter of the gene Y and activates Y (Y*) as a result of which gene Y gets expressed. Since Y should reach the activation threshold, to Joint Initiative of IITs and IISc Funded by MHRD Page 4 of 10

5 bind to the promoter of gene Z (indirect path), the process requires time. Hence delaying the expression of Z. Case 3: Sx OFF state In the AND circuit, when Sx is OFF, it cannot trigger the expression of Z directlu or through Y. Hence there is no expression of gene Z. In an OR function, when Sx is OFF, the transcription factor of the protein X does not become active X* and does not bind to the promoter of gene Z and gene Z is not expressed(direct path). The protein X does not binds to promoter of the gene Y and gene Y is not fully expressed. When Y reaches the activation threshold, it binds to the promoter of gene Z (indirect path). Since the levels of expression of Y isles in this case, the process is delayed and so is the expression of gene Z. Case 4: Inverted Out In both AND circuit, when the system is inverted, this case results in no expression of Z. Similarly OR gate can be worked out for all the four cases. 1.2 Coherent Feed Forward Loop type II (CFFL II) Fig 2 (b) Coherent Feed Forward Loop Type II (CFFL II) Table 2 (b) AND- and OR- gates at the Z promoter for CFFL II Joint Initiative of IITs and IISc Funded by MHRD Page 5 of 10

6 Case 1: Steady state In the AND circuit, the system reaches a steady state when S X^ (the inverted input signal of S X ) and signal S Y are present. In the presence of Sx^ signal, the active part of the transcription factor X which is X * binds to the promoter of gene Z through gene Y and also binds to gene Z independent of gene Y. Hence both the genes are expressed in this case. In an OR circuit, the system requires only the inverted signal Sx (Sx^) to reach steady state. Case 2: S X ON state In an AND circuit, when S X is ON, there is no gene expression. The activated protein X* also binds to promoter of the gene Y and represses gene Y. But Y reaches the activation threshold K and binds to the promoter of gene Z (indirect path). Since this process requires time for Y to reach the threshold. The expression of gene Z is delayed. Case 3: S X OFF state In the AND circuit, when S X is OFF, the transcription factor of the protein X does not get activated X* and hence does not bind to the promoter of gene Z. Hence is not repressed (direct path). The transcription factor of the protein X does not bind to promoter of the gene Y and gene Y is also not repressed. Y reaches the activation threshold, it binds to the promoter of gene Z (indirect path). Since this process depends on the activation of Y and the time required to reach the threshold. The expression of gene Z is delayed. Case 4: Inverted Out In both AND circuit, when the system is inverted, there is expression of gene Z without any delay, as its gene expression is controlled by the active X*(direct path). Joint Initiative of IITs and IISc Funded by MHRD Page 6 of 10

7 Similarly OR circuit can be worked out for all the four cases. 1.3 Coherent Feed Forward Loop type III (CFFL III) Fig 3 (c) Coherent Feed Forward Loop Type III (CFFL III) Table 3 (c) AND- and OR- gates at the Z promoter for CFFL III Case 1: Steady state: In the AND circuit, the system reaches steady state when the signals inverted S X is present. In the presence of inverted Sx signal, the active part of the transcription factor of X which is X * binds to the promoter of gene Z. Case 2: S X ON state In an AND, when Sx is ON, there is no gene expression of Z. Case 3: S X OFF state In an AND circuit, when S X is OFF, the transcription factor of the protein X cannot make an active X*and hence does not bind to the promoter of gene Z and gene Z is not repressed (direct path). The transcription factor of the protein X does not bind to promoter of the gene Y and gene Y is also not expressed. Hence gene Y will not repress gene Z because there is no production of Y (indirect path). The expression of gene Z is delayed. Joint Initiative of IITs and IISc Funded by MHRD Page 7 of 10

8 Case 4: Inverted Out In both AND circuit and OR circuit, when the system is inverted, there is expression of gene Z with delay, as its gene expression is controlled only by the active X* (direct path). Similarly OR circuit can be worked out for all the four cases. 1.4 Coherent Feed Forward Loop type IV (CFFL IV) Fig 4 (d) Coherent Feed Forward Loop Type IV (CFFL IV) Table 4 (d) AND- and OR- gates at the Z promoter for CFFL IV Case 1: Steady State In an AND circuit, the system reaches steady state when the signal S X is present. In the presence of the signal S X, the active part of the transcription factor of X which is X * binds to the promoter of both gene Z through gene Y and also to gene Z independent of gene Y. Therefore gene Z is expressed even when gene Y is repressed. The repression of gene Z does not take place through gene Y. Case 2: S X ON state In both AND circuits, when S X is on, the transcription factor of the protein X becomes active X*and binds to the promoter of gene Z and expresses gene Z (direct path).the activated protein X* also binds to promoter of the gene Y and represses gene Y. The Joint Initiative of IITs and IISc Funded by MHRD Page 8 of 10

9 repression of gene Z does not take place through Y. So the expression of gene Z is delayed. Case 3: S X OFF state In both AND circuit, when S X is OFF, there is no gene expression. Case 4: Inverted Out In both AND circuit, when the system is inverted, there is no expression of gene Z. Similarly OR circuit can be worked out all the four cases. Besides the logic functions and truth tables discussed elaborately in this lesson, Coherent Feed Forward Loops have well interesting properties in biological systems. An outstanding example is the function of Type-1 AND gate Coherent FFL as a sign sensitive delay in the arabinose system in E.coli in the presence of cyclic AMP signals. We shall deal with these in the next few classes which bring out a clear understanding of the information processing roles of the biological networks. Joint Initiative of IITs and IISc Funded by MHRD Page 9 of 10

10 2 References 2.1 Text Book 1. Uri Alon, An Introduction to Systems Biology: Design Principles of Biological Circuits, 2/e, CRC Press, (2006). 1.2 Literature References 1. Shai S. Shen-Orr, Ron Milo, Shmoolik Mangan & Uri Alon, Network motifs in the transcriptional regulation network of Escherichia coli, Nature Genetics, (2002), 31, S. Mangan and U. Alon, Structure and function of the feed-forward loop network motif, PNAS, (2003), 100, Shen-Orr, S., Milo R et al., Network motifs in the transcriptional regulation network of Escherichia coli, J.Mol. Biol., (2003), 334, Joint Initiative of IITs and IISc Funded by MHRD Page 10 of 10