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第408行： − − ==Well-established motifs and their functions== − Much experimental work has been devoted to understanding network motifs in [[gene regulatory networks]]. These networks control which genes are expressed in the cell in response to biological signals. The network is defined such that genes are nodes, and directed edges represent the control of one gene by a transcription factor (regulatory protein that binds DNA) encoded by another gene. Thus, network motifs are patterns of genes regulating each other's transcription rate. When analyzing transcription networks, it is seen that the same network motifs appear again and again in diverse organisms from bacteria to human. The transcription network of ''[[Escherichia coli|E. coli]]'' and yeast, for example, is made of three main motif families, that make up almost the entire network. The leading hypothesis is that the network motif were independently selected by evolutionary processes in a converging manner,<ref name="bab1">{{cite journal |vauthors=Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA |title=Structure and evolution of transcriptional regulatory networks |journal=Current Opinion in Structural Biology |volume=14 |issue=3 |pages=283–91 |date=June 2004 |pmid=15193307 |doi=10.1016/j.sbi.2004.05.004 |citeseerx=10.1.1.471.9692 }}</ref><ref name="con1">{{cite journal |vauthors=Conant GC, Wagner A |title=Convergent evolution of gene circuits |journal=Nat. Genet. |volume=34 |issue=3 |pages=264–6 |date=July 2003 |pmid=12819781 |doi=10.1038/ng1181}}</ref> since the creation or elimination of regulatory interactions is fast on evolutionary time scale, relative to the rate at which genes change,<ref name="bab1"/><ref name="con1"/><ref name="dek1">{{cite journal |vauthors=Dekel E, Alon U |title=Optimality and evolutionary tuning of the expression level of a protein |journal=Nature |volume=436 |issue=7050 |pages=588–92 |date=July 2005 |pmid=16049495 |doi=10.1038/nature03842 |bibcode=2005Natur.436..588D }}</ref> Furthermore, experiments on the dynamics generated by network motifs in living cells indicate that they have characteristic dynamical functions. This suggests that the network motif serve as building blocks in gene regulatory networks that are beneficial to the organism. − − The functions associated with common network motifs in transcription networks were explored and demonstrated by several research projects both theoretically and experimentally. Below are some of the most common network motifs and their associated function. − − ===Negative auto-regulation (NAR)=== − [[Image:Autoregulation motif.png|thumb|Schematic representation of an auto-regulation motif]] − One of simplest and most abundant network motifs in ''[[Escherichia coli|E. coli]]'' is negative auto-regulation in which a transcription factor (TF) represses its own transcription. This motif was shown to perform two important functions. The first function is response acceleration. NAR was shown to speed-up the response to signals both theoretically <ref name="zab1">{{cite journal |doi=10.1016/j.jtbi.2011.06.021 |author=Zabet NR |title=Negative feedback and physical limits of genes |journal=Journal of Theoretical Biology |volume= 284|issue=1 |pages=82–91 |date=September 2011 |pmid=21723295 |arxiv=1408.1869 |citeseerx=10.1.1.759.5418 }}</ref> and experimentally. This was first shown in a synthetic transcription network<ref name="ros1">{{cite journal |doi=10.1016/S0022-2836(02)00994-4 |vauthors=Rosenfeld N, Elowitz MB, Alon U |title=Negative autoregulation speeds the response times of transcription networks |journal=J. Mol. Biol. |volume=323 |issue=5 |pages=785–93 |date=November 2002 |pmid=12417193 |citeseerx=10.1.1.126.2604 }}</ref> and later on in the natural context in the SOS DNA repair system of E .coli.<ref name="cam1">{{cite journal |vauthors=Camas FM, Blázquez J, Poyatos JF |title=Autogenous and nonautogenous control of response in a genetic network |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=34 |pages=12718–23 |date=August 2006 |pmid=16908855 |pmc=1568915 |doi=10.1073/pnas.0602119103 |bibcode=2006PNAS..10312718C }}</ref> The second function is increased stability of the auto-regulated gene product concentration against stochastic noise, thus reducing variations in protein levels between different cells.<ref name="bec1">{{cite journal |vauthors=Becskei A, Serrano L |title=Engineering stability in gene networks by autoregulation |journal=Nature |volume=405 |issue=6786 |pages=590–3 |date=June 2000 |pmid=10850721 |doi=10.1038/35014651}}</ref><ref name="dub1">{{cite journal |vauthors=Dublanche Y, Michalodimitrakis K, Kümmerer N, Foglierini M, Serrano L |title=Noise in transcription negative feedback loops: simulation and experimental analysis |journal=Mol. Syst. Biol. |volume=2 |pages=41 |year=2006 |pmid=16883354 |pmc=1681513 |doi=10.1038/msb4100081 |issue=1}}</ref><ref name="shi1">{{cite journal |vauthors=Shimoga V, White J, Li Y, Sontag E, Bleris L |title= Synthetic mammalian transgene negative autoregulation |journal=Mol. Syst. Biol. |volume=9 |pages=670 |year=2013|doi=10.1038/msb.2013.27|pmid= 23736683 |pmc= 3964311 }}</ref> − − − − ===Positive auto-regulation (PAR)=== − Positive auto-regulation (PAR) occurs when a transcription factor enhances its own rate of production. Opposite to the NAR motif this motif slows the response time compared to simple regulation.<ref name="mae1">{{cite journal |vauthors=Maeda YT, Sano M |title=Regulatory dynamics of synthetic gene networks with positive feedback |journal=J. Mol. Biol. |volume=359 |issue=4 |pages=1107–24 |date=June 2006 |pmid=16701695 |doi=10.1016/j.jmb.2006.03.064 }}</ref> In the case of a strong PAR the motif may lead to a bimodal distribution of protein levels in cell populations.<ref name="bec2">{{cite journal |vauthors=Becskei A, Séraphin B, Serrano L |title=Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion |journal=EMBO J. |volume=20 |issue=10 |pages=2528–35 |date=May 2001 |pmid=11350942 |pmc=125456 |doi=10.1093/emboj/20.10.2528}}</ref> − − ===Feed-forward loops (FFL)=== − [[Image:Feed-forward motif.GIF|thumb|Schematic representation of a Feed-forward motif]] − This motif is commonly found in many gene systems and organisms. The motif consists of three genes and three regulatory interactions. The target gene C is regulated by 2 TFs A and B and in addition TF B is also regulated by TF A . Since each of the regulatory interactions may either be positive or negative there are possibly eight types of FFL motifs.<ref name="man1">{{cite journal |vauthors=Mangan S, Alon U |title=Structure and function of the feed-forward loop network motif |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=21 |pages=11980–5 |date=October 2003 |pmid=14530388 |pmc=218699 |doi=10.1073/pnas.2133841100 |bibcode=2003PNAS..10011980M }}</ref> Two of those eight types: the coherent type 1 FFL (C1-FFL) (where all interactions are positive) and the incoherent type 1 FFL (I1-FFL) (A activates C and also activates B which represses C) are found much more frequently in the transcription network of ''[[Escherichia coli|E. coli]]'' and yeast than the other six types.<ref name="man1"/><ref name="ma1">{{cite journal |vauthors=Ma HW, Kumar B, Ditges U, Gunzer F, Buer J, Zeng AP |title=An extended transcriptional regulatory network of ''Escherichia coli'' and analysis of its hierarchical structure and network motifs |journal=Nucleic Acids Res. |volume=32 |issue=22 |pages=6643–9 |year=2004 |pmid=15604458 |pmc=545451 |doi=10.1093/nar/gkh1009 |url=http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15604458}}</ref> In addition to the structure of the circuitry the way in which the signals from A and B are integrated by the C promoter should also be considered. In most of the cases the FFL is either an AND gate (A and B are required for C activation) or OR gate (either A or B are sufficient for C activation) but other input function are also possible. − − ===Coherent type 1 FFL (C1-FFL)=== − The C1-FFL with an AND gate was shown to have a function of a ‘sign-sensitive delay’ element and a persistence detector both theoretically <ref name="man1"/> and experimentally<ref name="man2">{{cite journal |doi=10.1016/j.jmb.2003.09.049 |vauthors=Mangan S, Zaslaver A, Alon U |title=The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks |journal=J. Mol. Biol. |volume=334 |issue=2 |pages=197–204 |date=November 2003 |pmid=14607112 |citeseerx=10.1.1.110.4629 }}</ref> with the arabinose system of ''[[Escherichia coli|E. coli]]''. This means that this motif can provide pulse filtration in which short pulses of signal will not generate a response but persistent signals will generate a response after short delay. The shut off of the output when a persistent pulse is ended will be fast. The opposite behavior emerges in the case of a sum gate with fast response and delayed shut off as was demonstrated in the flagella system of ''[[Escherichia coli|E. coli]]''.<ref name="kal1">{{cite journal |vauthors=Kalir S, Mangan S, Alon U |title=A coherent feed-forward loop with a SUM input function prolongs flagella expression in ''Escherichia coli'' |journal=Mol. Syst. Biol. |volume=1 |pages=E1–E6 |year=2005 |pmid=16729041 |pmc=1681456 |doi=10.1038/msb4100010 |issue=1}}</ref> De novo evolution of C1-FFLs in [[gene regulatory network]]s has been demonstrated computationally in response to selection to filter out an idealized short signal pulse, but for non-idealized noise, a dynamics-based system of feed-forward regulation with different topology was instead favored.<ref>{{cite journal |last1=Xiong |first1=Kun |last2=Lancaster |first2=Alex K. |last3=Siegal |first3=Mark L. |last4=Masel |first4=Joanna |title=Feed-forward regulation adaptively evolves via dynamics rather than topology when there is intrinsic noise |journal=Nature Communications |date=3 June 2019 |volume=10 |issue=1 |pages=2418 |doi=10.1038/s41467-019-10388-6|pmid=31160574 |pmc=6546794 }}</ref> − − ===Incoherent type 1 FFL (I1-FFL)=== − The I1-FFL is a pulse generator and response accelerator. The two signal pathways of the I1-FFL act in opposite directions where one pathway activates Z and the other represses it. When the repression is complete this leads to a pulse-like dynamics. It was also demonstrated experimentally that the I1-FFL can serve as response accelerator in a way which is similar to the NAR motif. The difference is that the I1-FFL can speed-up the response of any gene and not necessarily a transcription factor gene.<ref name="man3">{{cite journal |vauthors=Mangan S, Itzkovitz S, Zaslaver A, Alon U |title=The incoherent feed-forward loop accelerates the response-time of the gal system of ''Escherichia coli'' |journal=J. Mol. Biol. |volume=356 |issue=5 |pages=1073–81 |date=March 2006 |pmid=16406067 |doi=10.1016/j.jmb.2005.12.003 |citeseerx=10.1.1.184.8360 }}</ref> An additional function was assigned to the I1-FFL network motif: it was shown both theoretically and experimentally that the I1-FFL can generate non-monotonic input function in both a synthetic <ref name="ent1">{{cite journal |vauthors=Entus R, Aufderheide B, Sauro HM |title=Design and implementation of three incoherent feed-forward motif based biological concentration sensors |journal=Syst Synth Biol |volume=1 |issue=3 |pages=119–28 |date=August 2007 |pmid=19003446 |pmc=2398716 |doi=10.1007/s11693-007-9008-6 }}</ref> and native systems.<ref name="kap1">{{cite journal |vauthors=Kaplan S, Bren A, Dekel E, Alon U |title=The incoherent feed-forward loop can generate non-monotonic input functions for genes |journal=Mol. Syst. Biol. |volume=4 |pages=203 |year=2008 |pmid=18628744 |pmc=2516365 |doi=10.1038/msb.2008.43 |issue=1}}</ref> Finally, expression units that incorporate incoherent feedforward control of the gene product provide adaptation to the amount of DNA template and can be superior to simple combinations of constitutive promoters.<ref name="ble1">{{cite journal |vauthors=Bleris L, Xie Z, Glass D, Adadey A, Sontag E, Benenson Y |title=Synthetic incoherent feedforward circuits show adaptation to the amount of their genetic template |journal=Mol. Syst. Biol. |volume=7 |pages=519|year=2011 |doi=10.1038/msb.2011.49 |issue=1 |pmid=21811230 |pmc=3202791}}</ref> Feedforward regulation displayed better adaptation than negative feedback, and circuits based on RNA interference were the most robust to variation in DNA template amounts.<ref name="ble1"/> − − ===Multi-output FFLs=== − In some cases the same regulators X and Y regulate several Z genes of the same system. By adjusting the strength of the interactions this motif was shown to determine the temporal order of gene activation. This was demonstrated experimentally in the flagella system of ''[[Escherichia coli|E. coli]]''.<ref name="kal2">{{cite journal |vauthors=Kalir S, McClure J, Pabbaraju K, etal |title=Ordering genes in a flagella pathway by analysis of expression kinetics from living bacteria |journal=Science |volume=292 |issue=5524 |pages=2080–3 |date=June 2001 |pmid=11408658 |doi=10.1126/science.1058758 }}</ref> − − ===Single-input modules (SIM)=== − This motif occurs when a single regulator regulates a set of genes with no additional regulation. This is useful when the genes are cooperatively carrying out a specific function and therefore always need to be activated in a synchronized manner. By adjusting the strength of the interactions it can create temporal expression program of the genes it regulates.<ref name="zas1">{{cite journal |vauthors=Zaslaver A, Mayo AE, Rosenberg R, etal |title=Just-in-time transcription program in metabolic pathways |journal=Nat. Genet. |volume=36 |issue=5 |pages=486–91 |date=May 2004 |pmid=15107854 |doi=10.1038/ng1348|doi-access=free }}</ref> − − In the literature, Multiple-input modules (MIM) arose as a generalization of SIM. However, the precise definitions of SIM and MIM have been a source of inconsistency. There are attempts to provide orthogonal definitions for canonical motifs in biological networks and algorithms to enumerate them, especially SIM, MIM and Bi-Fan (2x2 MIM).<ref>{{cite journal |vauthors=Konagurthu AS, Lesk AM |title=Single and Multiple Input Modules in regulatory networks |journal=Proteins |volume=73 |issue=2 |pages=320–324 |year=2008 |doi=10.1002/prot.22053|pmid=18433061 }}</ref> − − ===Dense overlapping regulons (DOR)=== − This motif occurs in the case that several regulators combinatorially control a set of genes with diverse regulatory combinations. This motif was found in ''[[Escherichia coli|E. coli]]'' in various systems such as carbon utilization, anaerobic growth, stress response and others.<ref name="she1"/><ref name="boy1"/> In order to better understand the function of this motif one has to obtain more information about the way the multiple inputs are integrated by the genes. Kaplan ''et al.''<ref name="kap2">{{cite journal |vauthors=Kaplan S, Bren A, Zaslaver A, Dekel E, Alon U |title=Diverse two-dimensional input functions control bacterial sugar genes |journal=Mol. Cell |volume=29 |issue=6 |pages=786–92 |date=March 2008 |pmid=18374652 |pmc=2366073 |doi=10.1016/j.molcel.2008.01.021 }}</ref> has mapped the input functions of the sugar utilization genes in ''[[Escherichia coli|E. coli]]'', showing diverse shapes.
→Well-established motifs and their functions
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==已知的模体及其功能==
==已知的模体及其功能==