Regine Hengge

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany

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Publications (55)306.51 Total impact

  • Regine Hengge
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    ABSTRACT: What makes a multicellular aggregate of bacterial cells a biofilm is the presence of an extracellular polymeric matrix. Besides being protective, matrix components such as amyloid curli fibres and cellulose in Escherichia coli also assemble into a complex architecture that is controlled by RpoS and c-di-GMP. This confers extreme cohesion and elasticity to macrocolony biofilms. As a consequence, these biofilms behave like tissues, i. e. they buckle up into intricate morphological structures during growth.
    No preview · Article · Sep 2015 · BioSpektrum
  • Tatyana L Povolotsky · Regine Hengge
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    ABSTRACT: Importance: Our analysis reveals interesting trends in pathogenic E. coli that could reflect different host cell adherence mechanisms. These may either benefit from or be counteracted by the c-di-GMP-stimulated production of amyloid curli fibres and cellulose. Thus, EAEC - which adhere in a 'stacked brick' biofilm mode - have a potential for high c-di-GMP accumulation due to DgcX, a strongly expressed additional DGC. By contrast, EHEC and UPEC - which use alternative adherence mechanisms - tend to have extra PDEs, suggesting that low cellular c-di-GMP levels are crucial for these strains under some specific conditions. Overall, our study also indicates that GGDEF/EAL domain proteins evolve rapidly and thereby contribute to adaptation to host-specific and environmental niches of various types of E. coli.
    No preview · Article · Aug 2015 · Journal of bacteriology
  • Diego O Serra · Gisela Klauck · Regine Hengge
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    ABSTRACT: Bacterial macrocolony biofilms grow into intricate three-dimensional structures that depend on self-produced extracellular polymers conferring protection, cohesion and elasticity to the biofilm. In Escherichia coli, synthesis of this matrix - consisting of amyloid curli fibres and cellulose - requires CsgD, a transcription factor regulated by the stationary phase sigma factor RpoS, and occurs in the nutrient-deprived cells of the upper layer of macrocolonies. Is this asymmetric matrix distribution functionally important or is it just a fortuitous byproduct of an unavoidable nutrient gradient? In order to address this question, the RpoS-dependent csgD promoter was replaced by a vegetative promoter. This rewiring of csgD led to CsgD and matrix production in both strata of macrocolonies, with the lower layer transforming into a rigid 'baseplate' of growing, yet curli-connected cells. As a result, the two strata broke apart followed by desiccation and exfoliation of the top layer. By contrast, matrix-free cells at the bottom of wildtype macrocolonies maintain colony contact with the humid agar support by flexibly filling the space that opens up under buckling areas of the macrocolony. Precisely regulated stratification in matrix-free and matrix-producing cell layers is thus essential for the physical integrity and architecture of E. coli macrocolony biofilms. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Environmental Microbiology
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    ABSTRACT: Background Bacteria have developed a repertoire of signalling mechanisms that enable adaptive responses to fluctuating environmental conditions. The formation of biofilm, for example, allows persisting in times of external stresses, e.g. induced by antibiotics or a lack of nutrients. Adhesive curli fibers, the major extracellular matrix components in Escherichia coli biofilms, exhibit heterogeneous expression in isogenic cells exposed to identical external conditions. The dynamical mechanisms underlying this heterogeneity remain poorly understood. In this work, we elucidate the potential role of post-translational bistability as a source for this heterogeneity. Results We introduce a structured modelling workflow combining logical network topology analysis with time-continuous deterministic and stochastic modelling. The aim is to evaluate the topological structure of the underlying signalling network and to identify and analyse model parameterisations that satisfy observations from a set of genetic knockout experiments. Our work supports the hypothesis that the phenotypic heterogeneity of curli expression in biofilm cells is induced by bistable regulation at the post-translational level. Stochastic modelling suggests diverse noise-induced switching behaviours between the stable states, depending on the expression levels of the c-di-GMP-producing (diguanylate cyclases, DGCs) and -degrading (phosphodiesterases, PDEs) enzymes and reveals the quantitative difference in stable c-di-GMP levels between distinct phenotypes. The most dominant type of behaviour is characterised by a fast switching from curli-off to curli-on with a slow switching in the reverse direction and the second most dominant type is a long-term differentiation into curli-on or curli-off cells. This behaviour may implicate an intrinsic feature of the system allowing for a fast adaptive response (curli-on) versus a slow transition to the curli-off state, in line with experimental observations. Conclusion The combination of logical and continuous modelling enables a thorough analysis of different determinants of bistable regulation, i.e. network topology and biochemical kinetics, and allows for an incorporation of experimental data from heterogeneous sources. Our approach yields a mechanistic explanation for the phenotypic heterogeneity of curli fiber expression. Furthermore, the presented work provides a detailed insight into the interactions between the multiple DGC- and PDE-type enzymes and the role of c-di-GMP in dynamical regulation of cellular decisions. Electronic supplementary material The online version of this article (doi:10.1186/s12918-015-0183-x) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jul 2015 · BMC Systems Biology
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    ABSTRACT: In recent years, Escherichia coli has served as one of a handful of model bacterial species for studying c-di-GMP signaling. The widely used E. coli K-12 laboratory strains possesses 29 genes encoding proteins with GGDEF and/or EAL domains, which include 12 diguanylate cyclases (DGC), 13 c-di-GMP-specific phosphodiesterases (PDE) and four 'degenerate' enzymatically inactive proteins. In addition, six new GGDEF/EAL domain-encoding genes, which encode two DGCs and four PDEs, have recently been found in genomic analyses of commensal and pathogenic E. coli strains. As a group of researchers who have been studying the molecular mechanisms and/or the genomic basis of c-di-GMP signaling in E. coli, we now propose a general and systematic dgc and pde nomenclature for the enzymatically active GGDEF/EAL domain-encoding genes of this model species. This nomenclature is intuitive and easy to memorize and it can also be applied to additional genes and proteins that might be discovered in various strains of E. coli in future studies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Jul 2015 · Journal of bacteriology
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    ABSTRACT: The first 'International Symposium on c-di-GMP Signaling in Bacteria' (March 22 - 25, 2015, Harnack-Haus, Berlin, Germany) brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide second messenger signaling. While the focus was on signal input, synthesis, degradation and the striking diversity of the modes of action of the current second messenger paradigm, i.e. c-di-GMP, also 'classics' like cAMP and (p)ppGpp were presented in novel facets and more recent 'newcomers' such as c-di-AMP and c-AMP-GMP made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters and in the lively discussions, including (i) c-di-GMP control of the activities of various ATPases and phosphorylation cascades; (ii) extensive cross-talk between c-di-GMP and other nucleotide second messenger signaling pathways; and (iii) a stunning number of novel effectors for nucleotide second messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that second messenger signaling is currently one of the most dynamic fields within molecular microbiology with major impact ranging from human health to microbial ecology. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Jun 2015 · Journal of bacteriology
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    ABSTRACT: In 2011, nearly 4,000 people in Germany were infected by Shiga toxin (Stx)-producing Escherichia coli O104:H4 with > 22% of patients developing haemolytic uraemic syndrome (HUS). Genome sequencing showed the outbreak strain to be related to enteroaggregative E. coli (EAEC), suggesting its high virulence results from EAEC-typical strong adherence and biofilm formation combined to Stx production. Here, we report that the outbreak strain contains a novel diguanylate cyclase (DgcX)—producing the biofilm-promoting second messenger c-di-GMP—that shows higher expression than any other known E. coli diguanylate cyclase. Unlike closely related E. coli, the outbreak strain expresses the c-di-GMP-controlled biofilm regulator CsgD and amyloid curli fibres at 37°C, but is cellulose-negative. Moreover, it constantly generates derivatives with further increased and deregulated production of CsgD and curli. Since curli fibres are strongly proinflammatory, with cellulose counteracting this effect, high c-di-GMP and curli production by the outbreak O104:H4 strain may enhance not only adherence but may also contribute to inflammation, thereby facilitating entry of Stx into the bloodstream and to the kidneys where Stx causes HUS.
    Full-text · Article · Oct 2014 · EMBO Molecular Medicine
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    Franziska Mika · Regine Hengge
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    ABSTRACT: Amyloid curli fibers and cellulose are extracellular matrix components produced in the stationary phase top layer of E. coli macrocolonies, which confer physical protection, strong cohesion, elasticity, and wrinkled morphology to these biofilms. Curli and cellulose synthesis is controlled by a three-level transcription factor (TF) cascade with the RpoS sigma subunit of RNA polymerase at the top, the MerR-like TF MlrA, and the biofilm regulator CsgD, with two c-di-GMP control modules acting as key switching devices. Additional signal input and fine-tuning is provided by an entire series of small RNAs-ArcZ, DsrA, RprA, McaS, OmrA/OmrB, GcvB, and RydC-that differentially control all three TF modules by direct mRNA interaction. This review not only summarizes the mechanisms of action of these sRNAs, but also addresses the question of how these sRNAs and the regulators they target contribute to building the intriguing three-dimensional microarchitecture and macromorphology of these biofilms.
    Preview · Article · Apr 2014 · RNA Biology
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    Diego O. Serra · Regine Hengge
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    ABSTRACT: In natural habitats bacteria often occur in multicellular communities characterized by a robust extracellular matrix of proteins, amyloid fibres, exopolysaccharides and extracellular DNA. These biofilms show pronounced stress resistance including a resilience against antibiotics, which causes serious medical and technical problems. This review summarizes recent studies that have revealed clear spatial physiological differentiation, complex supracellular architecture and striking morphology in macrocolony biofilms. By responding to gradients of nutrients, oxygen, waste products and signaling compounds that build up in growing biofilms, various stress responses determine whether bacteria grow and proliferate or whether they enter into stationary phase and use their remaining resources for maintenance and survival. As a consequence, biofilms differentiate into at least two distinct layers of vegetatively growing and stationary phase cells that exhibit very different cellular physiology. This includes a stratification of matrix production with a major impact on microscopic architecture, biophysical properties and directly visible morphology of macrocolony biofilms. Using E. coli as a model system, this review also describes our detailed current knowledge about the underlying molecular control networks – prominently featuring sigma factors, transcriptional cascades and second messengers – that drive this spatial differentiation and points out directions for future research.
    Preview · Article · Apr 2014 · Environmental Microbiology
  • Regine Hengge

    No preview · Article · Dec 2013
  • Diego O Serra · Anja M Richter · Regine Hengge
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    ABSTRACT: Morphological form in multicellular aggregates emerges from the interplay of genetic constitution and environmental signals. Bacterial macrocolony biofilms, which form intricate three-dimensional structures such as large and often radially oriented ridges, concentric rings and elaborate wrinkles, provide a unique opportunity to understand this interplay of 'nature and nurture' in morphogenesis at the molecular level. Macrocolony morphology depends on self-produced extracellular matrix components. In Escherichia coli, these are stationary phase-induced amyloid curli fibres and cellulose. While the widely used 'domesticated' E. coli K-12 laboratory strains are unable to generate cellulose, we could restore cellulose production and macrocolony morphology of E. coli K-12 strain W3110 by 'repairing' a single chromosomal SNP in the bcs operon. Using scanning electron and fluorescence microscopy, cellulose filaments, sheets and nano-composites with curli fibres were localized in situ at cellular resolution within the physiologically two-layered macrocolony biofilms of this 'de-domesticated' strain. As an architectural element, cellulose confers cohesion and elasticity, i.e. tissue-like properties that - together with the cell-encasing curli fibre network and geometrical constraints in a growing colony - explain the formation of long and high ridges and elaborate wrinkles of wildtype macrocolonies. By contrast, a biofilm matrix consisting of the curli fibre network only is brittle and breaks into a pattern of concentric dome-shaped rings separated by deep crevices. These studies now set the stage for clarifying how regulatory networks and in particular c-di-GMP signaling operate in the three-dimensional space of highly structured and 'tissue-like' bacterial biofilms.
    No preview · Article · Oct 2013 · Journal of bacteriology
  • Regine Hengge · Victor Sourjik
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    ABSTRACT: The ESF-EMBO Conference on 'Bacterial Networks' (BacNet13) was held in March 2013, in Pultusk, Poland. It brought together 164 molecular microbiologists, bacterial systems biologists and synthetic biologists to discuss the architecture, function and dynamics of regulatory networks in bacteria.
    No preview · Article · Jul 2013 · EMBO Reports
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    ABSTRACT: C-di-GMP-which is produced by diguanylate cyclases (DGC) and degraded by specific phosphodiesterases (PDEs)-is a ubiquitous second messenger in bacterial biofilm formation. In Escherichia coli, several DGCs (YegE, YdaM) and PDEs (YhjH, YciR) and the MerR-like transcription factor MlrA regulate the transcription of csgD, which encodes a biofilm regulator essential for producing amyloid curli fibres of the biofilm matrix. Here, we demonstrate that this system operates as a signalling cascade, in which c-di-GMP controlled by the DGC/PDE pair YegE/YhjH (module I) regulates the activity of the YdaM/YciR pair (module II). Via multiple direct interactions, the two module II proteins form a signalling complex with MlrA. YciR acts as a connector between modules I and II and functions as a trigger enzyme: its direct inhibition of the DGC YdaM is relieved when it binds and degrades c-di-GMP generated by module I. As a consequence, YdaM then generates c-di-GMP and-by direct and specific interaction-activates MlrA to stimulate csgD transcription. Trigger enzymes may represent a general principle in local c-di-GMP signalling.
    Full-text · Article · May 2013 · The EMBO Journal
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    Franziska Mika · Regine Hengge
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    ABSTRACT: Biofilm formation in Escherichia coli and other enteric bacteria involves the inverse regulation of the synthesis of flagella and biofilm matrix components such as amyloid curli fibres, cellulose, colanic acid and poly-N-acetylglucosamine (PGA). Physiologically, these processes reflect the transition from growth to stationary phase. At the molecular level, they are tightly controlled by various sigma factors competing for RNA polymerase, a series of transcription factors acting in hierarchical regulatory cascades and several nucleotide messengers, including cyclic-di-GMP. In addition, a surprisingly large number of small regulatory RNAs (sRNAs) have been shown to directly or indirectly modulate motility and/or biofilm formation. This review aims at giving an overview of these sRNA regulators and their impact in biofilm formation in E. coli and Salmonella. Special emphasis will be put on sRNAs, that have known targets such as the mRNAs of the flagellar master regulator FlhDC, the stationary phase sigma factor σS (RpoS) and the key biofilm regulator CsgD that have recently been shown to act as major hubs for regulation by multiple sRNAs.
    Preview · Article · Mar 2013 · International Journal of Molecular Sciences
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    ABSTRACT: Unlabelled: Bacterial biofilms are highly structured multicellular communities whose formation involves flagella and an extracellular matrix of adhesins, amyloid fibers, and exopolysaccharides. Flagella are produced by still-dividing rod-shaped Escherichia coli cells during postexponential growth when nutrients become suboptimal. Upon entry into stationary phase, however, cells stop producing flagella, become ovoid, and generate amyloid curli fibers. These morphological changes, as well as accompanying global changes in gene expression and cellular physiology, depend on the induction of the stationary-phase sigma subunit of RNA polymerase, σ(S) (RpoS), the nucleotide second messengers cyclic AMP (cAMP), ppGpp, and cyclic-di-GMP, and a biofilm-controlling transcription factor, CsgD. Using flagella, curli fibers, a CsgD::GFP reporter, and cell morphology as "anatomical" hallmarks in fluorescence and scanning electron microscopy, different physiological zones in macrocolony biofilms of E. coli K-12 can be distinguished at cellular resolution. Small ovoid cells encased in a network of curli fibers form the outer biofilm layer. Inner regions are characterized by heterogeneous CsgD::GFP and curli expression. The bottom zone of the macrocolonies features elongated dividing cells and a tight mesh of entangled flagella, the formation of which requires flagellar motor function. Also, the cells in the outer-rim growth zone produce flagella, which wrap around and tether cells together. Adjacent to this growth zone, small chains and patches of shorter curli-surrounded cells appear side by side with flagellated curli-free cells before curli coverage finally becomes confluent, with essentially all cells in the surface layer being encased in "curli baskets." Importance: Heterogeneity or cellular differentiation in biofilms is a commonly accepted concept, but direct evidence at the microscale has been difficult to obtain. Our study reveals the microanatomy and microphysiology of an Escherichia coli macrocolony biofilm at an unprecedented cellular resolution, with physiologically different zones and strata forming as a function of known global regulatory networks that respond to biofilm-intrinsic gradients of nutrient supply. In addition, this study identifies zones of heterogeneous and potentially bistable CsgD and curli expression, shows bacterial curli networks to strikingly resemble Alzheimer plaques, and suggests a new role of flagella as an architectural element in biofilms.
    Full-text · Article · Feb 2013 · mBio
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    Regine Hengge

    Preview · Article · Feb 2013 · mBio
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    Regine Hengge
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    ABSTRACT: The ubiquitous bacterial second messenger bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) promotes biofilm formation by an astonishing variety of molecular mechanisms. Steiner et al (2013) now report that c-di-GMP directly stimulate interaction and enzymatic activity of two subunits of the membrane-integrated machinery that produces and secretes the poly-β-1,6-N-acetylglucosamine (PGA) exopolysaccharide in Escherichia coli.
    Preview · Article · Jan 2013 · The EMBO Journal
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    ABSTRACT: In response to the 2011 European health alert caused by a pathogenic Escherichia coli O104:H4 outbreak, the European Academy of Microbiology (EAM), established by the Federation of European Microbiological Societies (FEMS), convened a meeting in Paris on November 30th, 2011 on 'EHEC infection and control' attended by world renowned experts in pathogenic E. coli. The major aims of this group were to review the scientific issues raised by the outbreak, to assess the handling of the crisis at the scientific and political levels, and to propose future actions. Several conclusions, which will have impact on future potential E. coli outbreaks, are outlined here.
    Full-text · Article · Sep 2012 · EMBO Molecular Medicine
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    Natalia Tschowri · Sandra Lindenberg · Regine Hengge
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    ABSTRACT: Escherichia coli senses blue light via the BLUF-EAL protein BluF (YcgF). The degenerate EAL domain of BluF does not have cyclic-di-GMP phosphodiesterase activity, but BluF directly antagonizes the MerR-like repressor BluR (YcgE), which leads to expression of the ycgZ-ymgABC operon and activation of the Rcs system (Tschowri et al., 2009; Genes Dev 23: 522-534). While bluR, bluF and ycgZ have individual transcriptional start sites, comparative genome analysis indicates that the bluR-bluF-ycgZ-ymgAB region represents a functional unit in various enteric bacteria that is characterized by bluF alleles encoding degenerate EAL domains. Re-introducing conserved amino acids involved in phosphodiesterase activity of EAL domains did not restore enzymatic activity or c-di-GMP binding of BluF, but weakened its ability to antagonize BluR and improved a residual interaction with the BluR paralogue MlrA, which controls expression of the biofilm regulator CsgD and curli fibres. We identified the BluR binding site in the ycgZ promoter and observed that BluR also has residual affinity for the MlrA-dependent csgD promoter. Altogether, we propose that BluF evolved from a blue light-regulated PDE into a specific antagonist of a duplicate of MlrA that became BluR, which controls not only curli but various biofilm functions via the Ymg/Rcs pathway.
    Full-text · Article · Jul 2012 · Molecular Microbiology
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    ABSTRACT: RprA is a small regulatory RNA known to weakly affect the translation of σ(S) (RpoS) in Escherichia coli. Here we demonstrate that csgD, which encodes a stationary phase-induced biofilm regulator, as well as ydaM, which encodes a diguanylate cyclase involved in activating csgD transcription, are novel negatively controlled RprA targets. As shown by extensive mutational analysis, direct binding of RprA to the 5'-untranslated and translational initiation regions of csgD mRNA inhibits translation and reduces csgD mRNA levels. In the case of ydaM mRNA, RprA base-pairs directly downstream of the translational start codon. In a feedforward loop, RprA can thus downregulate > 30 YdaM/CsgD-activated genes including those for adhesive curli fimbriae. However, during early stationary phase, when csgD transcription is strongly activated, the synthesis of csgD mRNA exceeds that of RprA, which allows the accumulation of CsgD protein. This situation is reversed when csgD transcription is shut off - for instance, later in stationary phase or during biofilm formation - or by conditions that further activate RprA expression via the Rcs two-component system. Thus, antagonistic regulation of csgD and RprA at the mRNA level integrates cell envelope stress signals with global gene expression during stationary phase and biofilm formation.
    Full-text · Article · Feb 2012 · Molecular Microbiology

Publication Stats

3k Citations
306.51 Total Impact Points

Institutions

  • 2014-2015
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2003-2013
    • Freie Universität Berlin
      • Institute of Biology
      Berlín, Berlin, Germany
  • 2005
    • Forschungszentrum Jülich
      Jülich, North Rhine-Westphalia, Germany