Evolutionary potential of transcription factors for gene regulatory rewiring

Igler, Claudia; Lagator, Mato; Tkačik, Gašper; Bollback, Jonathan P.; Guet, Călin C.

doi:10.1038/s41559-018-0651-y

Cited by 31 publications

(35 citation statements)

References 69 publications

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“…The diverse range of infection phenotypes observed on lysogens or CRSs could be caused by several factors related to Rep expression and specificity. Immunity asymmetry may be caused by repressors with sufficiently similar, but distinct, binding affinities or specificities (39), combined with subtle differences in the sequences and positions of stoperators, such that only one of the repressors is able to prevent lytic gene expression in both genomes. Gradual fading of spot dilutions could reflect weak affinity or specificity of the prophage’s Rep for stoperators in the superinfecting phage genome that is sufficient to interfere with, but not completely defend against, superinfection and lytic growth, resulting in smaller or more turbid plaques and spots.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Superinfection Immunity in Cluster A Mycobacteriophages

Mavrich

Hatfull

2019

mBio

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Temperate phages encode an immunity system to control lytic gene expression during lysogeny. This gene regulatory circuit consists of multiple interacting genetic elements, and although it is essential for controlling phage growth, it is subject to conflicting evolutionary pressures. During superinfection of a lysogen, the prophage’s circuit interacts with the superinfecting phage’s circuit and prevents lytic growth if the two circuits are closely related. The circuitry is advantageous since it provides the prophage with a defense mechanism, but the circuitry is also disadvantageous since it limits the phage’s host range during superinfection. Evolutionarily related phages have divergent, orthogonal immunity systems that no longer interact and are heteroimmune, but we do not understand how immunity systems evolve new specificities. Here, we use a group of Cluster A mycobacteriophages that exhibit a spectrum of genetic diversity to examine how immunity system evolution impacts superinfection immunity. We show that phages with mesotypic (i.e., genetically related but distinct) immunity systems exhibit asymmetric and incomplete superinfection phenotypes. They form complex immunity networks instead of well-defined immunity groups, and mutations conferring escape (i.e., virulence) from homotypic or mesotypic immunity have various escape specificities. Thus, virulence and the evolution of new immune specificities are shaped by interactions with homotypic and mesotypic immunity systems. IMPORTANCE Many aspects regarding superinfection, immunity, virulence, and the evolution of immune specificities are poorly understood due to the lack of large collections of isolated and sequenced phages with a spectrum of genetic diversity. Using a genetically diverse collection of Cluster A phages, we show that the classical and relatively straightforward patterns of homoimmunity, heteroimmunity, and virulence result from interactions between homotypic and heterotypic phages at the extreme edges of an evolutionary continuum of immune specificities. Genetic interactions between mesotypic phages result in more complex mesoimmunity phenotypes and virulence profiles. These results highlight that the evolution of immune specificities can be shaped by homotypic and mesotypic interactions and may be more dynamic than previously considered.

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Section: Discussionmentioning

confidence: 99%

Evolution of Superinfection Immunity in Cluster A Mycobacteriophages

Mavrich

Hatfull

2019

mBio

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“…Changes in regulatory connections between individual transcriptional units (TUs) or, in other words, the rewiring of gene regulatory networks (GRNs), is a major genetic mechanism underlying phenotypic diversity (Shubin et al, 2009;Wagner and Lynch, 2010;Wray, 2007). A lot of effort has been put into understanding how mutations in transcription factors and their DNA binding sites within promoter regions influence GRN behavior, plasticity and evolution (Babu et al, 2004;Balaji et al, 2007;Chen et al, 2012;Igler et al, 2018;Isalan et al, 2008;Nocedal et al, 2017). However, we are still unable to predict GRN phenotypes from first principles (Browning and Busby, 2016).…”

Section: Introductionmentioning

confidence: 99%

Local genetic context shapes the function of a gene regulatory network

Staroń

Tomasek

Carter

et al. 2021

eLife

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Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions, such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks remains a major challenge. Here, we use a well-defined synthetic gene regulatory network to study in Escherichia coli how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one gene regulatory network with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Transcriptional read-through is the main molecular mechanism that places one transcriptional unit within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual transcriptional units, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of gene regulatory networks.

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“…Besides experimental studies of natural gene network evolution under controlled conditions [5,8,[17][18][19][20][21], synthetic gene circuits can serve as well-characterized models of natural stress-response modules in evolution experiments [9,22,23]. Well-controlled and tunable synthetic gene circuits that interact minimally with the host genome [24][25][26][27] can aid the interpretation of experimental outcomes.…”

Section: Introductionmentioning

confidence: 99%

Evolutionary regain of lost gene circuit function

Gouda

Manhart

Balazsi³

2019

Preprint

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Evolutionary reversibility -the ability to regain a lost function -is an important problem both in evolutionary and synthetic biology, where repairing natural or synthetic systems broken by evolutionary processes may be valuable. Here, we use a synthetic positivefeedback (PF) gene circuit integrated into haploid Saccharomyces cerevisiae cells to test if the population can restore lost PF function. In previous evolution experiments, mutations in a gene eliminated the fitness costs of PF activation. Since PF activation also provides drug resistance, exposing such compromised or broken mutants to both drug and inducer should create selection pressure to regain drug resistance and possibly PF function. Indeed, evolving seven PF mutant strains in the presence of drug revealed three adaptation scenarios through genomic mutations outside of the PF circuit that elevate PF basal expression, possibly by affecting transcription, translation, degradation and other fundamental cell functions. Nonfunctional mutants gained drug resistance without ever developing high expression, while quasi-functional and dysfunctional PF mutants developed high expression which then diminished, although more slowly for dysfunctional mutants where revertant clones arose. These results highlight how intracellular context, such as the growth rate, can affect regulatory network dynamics and evolutionary dynamics, which has important consequences for understanding the evolution of drug resistance and developing future synthetic biology applications. Significance Statement Natural or synthetic genetic modules can lose their function over long-term evolution if the function is costly. How populations can evolve to restore broken functions is poorly understood. To test the reversibility of evolutionary breakdown, we use yeast cell populations with a chromosomally integrated synthetic gene circuit. In previous evolution experiments the gene circuit lost its costly function through various mutations. By exposing such mutant populations to conditions where regaining gene circuit function would be beneficial we find adaptation scenarios with or without repairing lost gene circuit function. These results are important for drug resistance or future synthetic biology applications where loss and regain of function play a significant role.

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Evolutionary potential of transcription factors for gene regulatory rewiring

Cited by 31 publications

References 69 publications

Evolution of Superinfection Immunity in Cluster A Mycobacteriophages

Evolution of Superinfection Immunity in Cluster A Mycobacteriophages

Local genetic context shapes the function of a gene regulatory network

Evolutionary regain of lost gene circuit function

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