Bacterial Information transfer circuit for mammalian gut
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ABSTRACT:
PROVIDER: PRJEB28380 | ENA |
REPOSITORIES: ENA
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Project description:The mouse visual system serves as an accessible model to understand mammalian circuit wiring. Despite rich knowledge in retinal circuits, the long-range connectivity map from distinct retinal ganglion cell (RGC) types to diverse brain neuron types remains unknown. Here we developed an integrated approach, named Trans-Seq, to map RGC to superior collicular (SC) circuits. Trans-Seq combines a fluorescent anterograde transsynaptic tracer, consisting of codon-optimized wheat germ agglutinin fused to mCherry, with single-cell RNA Sequencing. We used Trans-Seq to classify SC neuron types innervated by genetically-defined RGC types and predicted a neuronal pair from αRGCs to Nephronectin-positive wide-field neurons (NPWFs). We validated this connection using genetic labeling, electrophysiology, and retrograde tracing. We then utilized transcriptomic data from Trans-Seq to identify Nephronectin as a determinant for selective synaptic choice from αRGC to NPWFs via binding to Integrin-α8β1. The Trans-Seq approach can be broadly applied for postsynaptic circuit discovery from genetically-defined presynaptic neurons.
2022-05-07 | GSE202257 | GEO
Project description:Glycan-binding proteins, so-called lectins, are exposed on mammalian cell surfaces and decipher the information encoded within glycans translating it into biochemical signal transduction pathways in the cell. These glycan-lectin communication pathways are complex and difficult to analyze. However, quantitative data with single-cell resolution provide means to disentangle the associated signaling cascades. We chose C-type lectin receptors (CTLs) expressed on immune cells as a model system to study their capacity to transmit information encoded in glycans of incoming particles. In particular, we used nuclear factor kappa-B-reporter cell lines expressing DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), macrophage C-type lectin (MCL), dectin-1, dectin-2, and macrophage-inducible C-type lectin (MINCLE), as well as TNFαR and TLR-1&2 in monocytic cell lines and compared their transmission of glycan-encoded information. All receptors transmit information with similar signaling capacity, except dectin-2. This lectin was identified to be less efficient in information transmission compared to the other CTLs, and even when the sensitivity of the dectin-2 pathway was enhanced by overexpression of its co-receptor FcRγ, its transmitted information was not. Next, we expanded our investigation toward the integration of multiple signal transduction pathways including synergistic lectins, which is crucial during pathogen recognition. We show how the signaling capacity of lectin receptors using a similar signal transduction pathway (dectin-1 and dectin-2) is being integrated by compromising between the lectins. In contrast, co-expression of MCL synergistically enhanced the dectin-2 signaling capacity, particularly at low-glycan stimulant concentration. By using dectin-2 and other lectins as examples, we demonstrate how signaling capacity of dectin-2 is modulated in the presence of other lectins, and therefore, the findings provide insight into how immune cells translate glycan information using multivalent interactions.
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Project description:In mammalian and bacterial cells simple phosphorylation circuits play an important role in signaling. Bacteria have hundreds of two-component signaling systems that involve phosphotransfer between a receptor and a response regulator. In mammalian cells a similar pathway is the TGF-beta pathway, where extracellular TGF-beta ligands activate cell surface receptors that phosphorylate Smad proteins, which in turn activate many genes. In TGF-beta signaling the multiplicity of ligands begs the question as to whether cells can distinguish signals coming from different ligands, but transduced through a small set of Smads. Here we use information theory with stochastic simulations of networks to address this question. We find that when signals are transduced through only one Smad, the cell cannot distinguish between different levels of the external ligands. Increasing the number of Smads from one to two significantly improves information transmission as well as the ability to discriminate between ligands. Surprisingly, both total information transmitted and the capacity to discriminate between ligands are quite insensitive to high levels of cross-talk between the two Smads. Robustness against cross-talk requires that the average amplitude of the signals are large. We find that smaller systems, as exemplified by some two-component systems in bacteria, are significantly much less robust against cross-talk. For such system sizes phosphotransfer is also less robust against cross-talk than phosphorylation. This suggests that mammalian signal transduction can tolerate a high amount of cross-talk without degrading information content. This may have played a role in the evolution of new functionalities from small mutations in signaling pathways, allowed for the development of cross-regulation and led to increased overall robustness due to redundancy in signaling pathways. On the other hand the lack of cross-regulation observed in many bacterial two-component systems may partly be due to the loss of information content due to cross-talk.
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Project description:Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit, yet the design features of cell circuits involved in tissue homeostasis are unknown. Here we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations. We employed analytical screening of all possible two-cell circuit topologies and defined the circuit features sufficient for stability, including environmental constraint and negative feedback regulation. Moreover, we discovered that cell-cell contact was essential for the stability of the macrophage-fibroblast circuit. These findings highlight general principles of cell circuit design, and provide a new perspective on quantitative understanding of tissue homeostasis.
2018-02-08 | GSE104511 | GEO
Project description:Mechanobiologic signals play critical roles in regulating cellular responses under both physiologic and pathologic conditions. Using a combination of synthetic biology and tissue engineering, we developed a mechanically-responsive bioartificial tissue that responds to mechanical loading to produce a pre-programmed therapeutic biologic drug. By deconstructing the signaling networks induced by activation the mechanically-sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we synthesized synthetic TRPV4-responsive genetic circuits in chondrocytes. These cells were then engineered into living tissues that respond to mechanical compression to drive the production of the anti-inflammatory drug interleukin-1 receptor antagonist. Mechanical loading of these tissues in the presence of the cytokine interleukin-1 protected constructs from inflammatory degradation. This “mechanogenetic” approach enables long-term autonomous delivery of therapeutic compounds that is driven by physiologically-relevant mechanical loading with cell-scale mechanical force resolution. The development of synthetic mechanogenetic gene circuits provides a novel approach for the autonomous regulation of cell-based drug delivery systems.
2021-01-19 | GSE165027 | GEO
Project description:In mammalian systems, extracellular small RNAs can operate in a paracrine manner to communicate information between cells, relying on transport within vesicles. “Foreign” small RNAs derived from bacteria, plants and parasites have also been detected in mammalian body fluids, sparking interest in whether these could mediate inter-species communication. However, there is no mechanistic framework for RNA-mediated interspecies communication and the active movement of RNA via vesicles has not been shown outside of mammals. Here we demonstrate that specific microRNAs and Y RNAs are packaged into vesicles secreted by a gastrointestinal nematode, Heligmosomoides polygyrus, which naturally infects mice. Total RNA was extracted from the serum of mice infected with Litomosoides sigmodontis at 60 days post infection
2014-11-26 | E-GEOD-60021 | biostudies-arrayexpress
Project description:In mammalian systems, extracellular small RNAs can operate in a paracrine manner to communicate information between cells, relying on transport within vesicles. “Foreign” small RNAs derived from bacteria, plants and parasites have also been detected in mammalian body fluids, sparking interest in whether these could mediate inter-species communication. However, there is no mechanistic framework for RNA-mediated interspecies communication and the active movement of RNA via vesicles has not been shown outside of mammals. Here we demonstrate that specific microRNAs and Y RNAs are packaged into vesicles secreted by a gastrointestinal nematode, Heligmosomoides polygyrus, which naturally infects mice. Total RNA was extracted from the secretion product of adult worms and compared to the profile of small RNAs in adult worms, eggs and infective larvae.
2014-11-25 | E-GEOD-55978 | biostudies-arrayexpress
Project description:Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression. Indeed, an annotated super-enhancer is dispensable for NEK6 overexpression and for maintaining the architecture of a B cell-specific regulatory hub. A CTCF cluster serves as a chromatin and architectural boundary to block communication of the NEK6 regulatory hub with neighboring genes. Our findings emphasize that validation of predicted cis-regulatory circuits and super-enhancers is needed to prioritize transcriptional control elements as therapeutic targets.
2017-02-23 | GSE87322 | GEO
Project description:Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression. Indeed, an annotated super-enhancer is dispensable for NEK6 overexpression and for maintaining the architecture of a B cell-specific regulatory hub. A CTCF cluster serves as a chromatin and architectural boundary to block communication of the NEK6 regulatory hub with neighboring genes. Our findings emphasize that validation of predicted cis-regulatory circuits and super-enhancers is needed to prioritize transcriptional control elements as therapeutic targets.
2017-02-23 | GSE87320 | GEO
Project description:The Bxb1 bacteriophage serine DNA recombinase is an efficient tool for engineering recombinant DNA into the genomes of cultured cells. Generally, a single engineered “landing pad” site is introduced into the cell genome, permitting the integration of transgenic circuits or libraries of transgene variants. While sufficient for many studies, the extent of genetic manipulation possible with a single recombinase site is limiting, and insufficient for more complex cell-based assays for protein function. Here, we harnessed two orthogonal Bxb1 recombinase sites to enable new avenues for mammalian synthetic biology. By designing plasmids with two recombinase sites, we demonstrate that we can avoid genomic integration of undesirable bacterial DNA elements. We also created “double landing pad” cells simultaneously harboring two orthogonal Bxb1 recombinase sites. These cells allow transgenic protein variant libraries to be readily paired with assay-specific protein partners or biosensors, opening up new functional readouts for large-scale functional assays.
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