A double-negative gene regulatory circuit underlies the virgin behavioral state

The survival and reproductive success of animals depends on the ability to harmonize their external behaviors with their internal states. For example, females conduct numerous social programs that are distinctive to virgins, compared to post-mated and/or pregnant individuals. In Drosophila, the fact that this post-mating switch is initiated by seminal factors implies that the default state is virgin. However, we recently showed that loss of miR-iab-4/8-mediated repression of the transcription factor Homothorax (Hth) within the abdominal ventral nerve cord (VNC) causes virgin females to execute mated behaviors. To elucidate new components of this post-transcriptional regulatory circuit, we used genomic analysis of mir-iab-4/8 deletion and hth-miRNA binding site mutants (hth[BSmut]) to elucidate doublesex (dsx) as a critical downstream factor. While Dsx has mostly been studied during sex-specific differentiation, its activities in neurons are little known. We find that accumulation of Dsx in the CNS is highly complementary to Hth, and downregulated in miRNA/hth[BSmut] mutants. Moreover, virgin behavior is highly dose-sensitive to developmental dsx function. Strikingly, depletion of Dsx in SAG-1 cells, a highly restricted set of abdominal neurons, abrogates female virgin conducts in favor of mated behavioral programs. Thus, a double negative post-transcriptional pathway in the VNC (miR-iab-4/8 -| Hth -| Dsx) specifies the virgin behavioral state.

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A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses

Nature ◽

10.1038/nature11428 ◽

2012 ◽

Vol 490 (7420) ◽

pp. 421-425 ◽

Cited By ~ 96

Author(s):

Vladimir Litvak ◽

Alexander V. Ratushny ◽

Aaron E. Lampano ◽

Frank Schmitz ◽

Albert C. Huang ◽

...

Keyword(s):

Antiviral Responses ◽

Regulatory Circuit ◽

Gene Regulatory

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Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

Eukaryotic Cell ◽

10.1128/ec.00137-13 ◽

2013 ◽

Vol 12 (9) ◽

pp. 1293-1304 ◽

Cited By ~ 26

Author(s):

Anda Zhang ◽

Zhongle Liu ◽

Lawrence C. Myers

Keyword(s):

Candida Albicans ◽

Ectopic Expression ◽

Small Subset ◽

Content Type ◽

Impaired Ability ◽

Transcriptional Effect ◽

Environmental Induction ◽

Gene Regulatory ◽

The Stability ◽

Negative Gene

ABSTRACT The multisubunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in Candida albicans as a model, we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bistable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits have shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency, and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady-state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. The MED16 and MED9 genes have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences.

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Noise effect on persistence of memory in a positive-feedback gene regulatory circuit

Physical Review E ◽

10.1103/physreve.80.011907 ◽

2009 ◽

Vol 80 (1) ◽

Cited By ~ 11

Author(s):

Jun Tang ◽

Xianqing Yang ◽

Jun Ma ◽

Ya Jia

Keyword(s):

Positive Feedback ◽

Noise Effect ◽

Regulatory Circuit ◽

Gene Regulatory

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Vibrio cholerae LexA Coordinates CTX Prophage Gene Expression

Journal of Bacteriology ◽

10.1128/jb.00682-09 ◽

2009 ◽

Vol 191 (22) ◽

pp. 6788-6795 ◽

Cited By ~ 20

Author(s):

Harvey H. Kimsey ◽

Matthew K. Waldor

Keyword(s):

Gene Expression ◽

Cholera Toxin ◽

Vibrio Cholerae ◽

Single Site ◽

Virion Production ◽

Regulatory Circuit ◽

Ctxφ Prophage ◽

Gene Regulatory ◽

Ctx Prophage ◽

Operator Site

ABSTRACT The filamentous bacteriophage CTXΦ transmits the cholera toxin genes by infecting and lysogenizing its host, Vibrio cholerae. CTXΦ genes required for virion production initiate transcription from the strong P A promoter, which is dually repressed in lysogens by the phage-encoded repressor RstR and the host-encoded SOS repressor LexA. Here we identify the neighboring divergent rstR promoter, P R, and show that RstR both positively and negatively autoregulates its own expression from this promoter. LexA is absolutely required for RstR-mediated activation of P R transcription. RstR autoactivation occurs when RstR is bound to an operator site centered 60 bp upstream of the start of transcription, and the coactivator LexA is bound to a 16-bp SOS box centered at position −23.5, within the P R spacer region. Our results indicate that LexA, when bound to its single site in the CTXΦ prophage, both represses transcription from P A and coactivates transcription from the divergent P R. We propose that LexA coordinates P A and P R prophage transcription in a gene regulatory circuit. This circuit is predicted to display transient switch behavior upon induction of CTXΦ lysogens.

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Dynamic modeling ofStreptococcus pneumoniaecompetence provides regulatory mechanistic insights

10.1101/300814 ◽

2018 ◽

Cited By ~ 1

Author(s):

Mathias Weyder ◽

Marc Prudhomme ◽

Mathieu Bergé ◽

Patrice Polard ◽

Gwennaele Fichant

Keyword(s):

Positive Feedback ◽

Feedback Loop ◽

Natural Transformation ◽

Transient State ◽

Ph Change ◽

Positive Feedback Loop ◽

Average Cell ◽

Knowledge Based ◽

Regulatory Circuit ◽

Gene Regulatory

AbstractIn the human pathogenStreptococcus pneumoniae, the gene regulatory circuit leading to the transient state of competence for natural transformation is based on production of an auto-inducer that activates a positive feedback loop. About one hundred genes are activated in two successive waves linked by a central alternative sigma factor ComX. This mechanism appears to be fundamental to the biological fitness ofS. pneumoniae.We have developed a knowledge-based model of the competence cycle that describes average cell behavior. It reveals that the expression rates of the two competence operon,comABandcomCDE, involved in the positive feedback loop must be coordinated to elicit spontaneous competence. Simulations revealed the requirement for an unknown latecomgene product that shuts of competence by impairing ComX activity. Further simulations led to the predictions that the membrane protein ComD bound to CSP reacts directly to pH change of the medium and that blindness to CSP during the post-competence phase is controlled by late DprA protein. Both predictions were confirmed experimentally.

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Genetic signatures of evolution of the pluripotency gene regulating network across mammals

10.1101/2020.04.16.043943 ◽

2020 ◽

Author(s):

Yoshinori Endo ◽

Ken-ichiro Kamei ◽

Miho Inoue-Murayama

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Mammalian Species ◽

Rapid Evolution ◽

Network Evolution ◽

Downstream Targets ◽

The Core ◽

Regulatory Circuit ◽

Pluripotency Gene ◽

Gene Regulatory

AbstractMammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics, but we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we applied a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We found evolutionary conservation in JAK-STAT and PI3K-Akt signaling pathways, suggesting equivalent capabilities in self-renewal and proliferation of mammalian PSCs. On the other hand, we discovered rapid evolution of the downstream targets of the core regulatory circuit, providing insights into variations of characteristics. Our data indicate that the variations in the PSCs characteristics may be due to positive selections in the downstream targets of the core regulatory circuit. We further reveal that positively selected genes can be associated with species unique adaptation that is not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

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Evolution of Superinfection Immunity in Cluster A Mycobacteriophages

mBio ◽

10.1128/mbio.00971-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 14

Author(s):

Travis N. Mavrich ◽

Graham F. Hatfull

Keyword(s):

Gene Expression ◽

Genetic Diversity ◽

Defense Mechanism ◽

Genetic Interactions ◽

Form Complex ◽

Lytic Gene ◽

Regulatory Circuit ◽

Gene Regulatory ◽

Cluster A ◽

Phage Growth

ABSTRACTTemperate 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.IMPORTANCEMany 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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Abstract 14745: The Histone Reader PHF7 Cooperates With the SWI/SNF Complex at Cardiac Super Enhancers to Promote Direct Cardiac Reprogramming

Circulation ◽

10.1161/circ.142.suppl_3.14745 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Glynnis A Garry ◽

Svetlana Bezprozvannaya ◽

Kenian Chen ◽

Huanyu Zhou ◽

Hisayuki Hashimoto ◽

...

Keyword(s):

Transcription Factors ◽

Chromatin Remodeling ◽

Therapeutic Strategy ◽

Chromatin Accessibility ◽

Epigenetic Factor ◽

Epigenetic Modifiers ◽

Regulatory Circuit ◽

Gene Regulatory ◽

Cardiac Transcription Factors ◽

Adult Fibroblasts

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Further, PHF7 recruits cardiac transcription factors to activate a core regulatory circuit in reprogramming. Importantly, PHF7 is the first epigenetic factor shown to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

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