Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma

Ijaz, Talha; Pazdrak, Konrad; Kalita, Mridul; König, Rolf; Choudhary, Sanjeev; Tian, Bing; Boldogh, István; Brasier, Allan R.

doi:10.1186/1939-4551-7-13

Cited by 103 publications

(106 citation statements)

References 117 publications

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“…Studies of systems and integrative biology address exactly these challenges, and are now emerging as critical in advancing all branches of biomedical science. Next generation sequencing technology, shared availability of “big data” and advances in computational biology are new promising tools for discovery of novel drivers of barrier dysfunction 150, 151 .…”

Section: Identifying Key Drivers Of Defects and The Basis For Prementioning

confidence: 99%

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Schleimer

Berdnikovs

2017

Journal of Allergy and Clinical Immunology

134

122

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Epithelial barriers of the skin, gastrointestinal tract and airway serve common critical functions such as maintaining a physical barrier against environmental insults and allergens, as well as providing a tissue interface balancing the communication between the internal and external environments. We now understand that in allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed towards loss of differentiation, reduced junctional integrity and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in the initiation of allergic disease, many important questions remain to be answered regarding the mechanisms disrupting the normal barrier function. Although our external environment (proteases, allergens, injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction, using both systems biology tools and causality-driven laboratory experimentation, will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergy.

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Section: Identifying Key Drivers Of Defects and The Basis For Prementioning

confidence: 99%

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Schleimer

Berdnikovs

2017

Journal of Allergy and Clinical Immunology

134

122

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“…We discovered modules enriched in action modes that point to how different processes modulating the activity of NF-jB/RelA. We generated an EMT contextspecific modulatory subnetwork comprising extracellular matrix formation, actin polymerization pathways, and long intergenic non-protein-coding RNA regulated by EMT (Ijaz et al, 2014). This information may provide potential drug targets for EMT-related cancer progression.…”

mentioning

confidence: 99%

Inferring Genome-Wide Functional Modulatory Network: A Case Study on NF-κB/RelA Transcription Factor

Zhu

Brasier

et al. 2015

Journal of Computational Biology

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How different pathways lead to the activation of a specific transcription factor (TF) with specific effects is not fully understood. We model context-specific transcriptional regulation as a modulatory network: triplets composed of a TF, target gene, and modulator. Modulators usually affect the activity of a specific TF at the posttranscriptional level in a target gene-specific action mode. This action may be classified as enhancement, attenuation, or inversion of either activation or inhibition. As a case study, we inferred, from a large collection of expression profiles, all potential modulations of NF-jB/RelA. The predicted modulators include many proteins previously not reported as physically binding to RelA but with relevant functions, such as RNA processing, cell cycle, mitochondrion, ubiquitindependent proteolysis, and chromatin modification. Modulators from different processes exert specific prevalent action modes on distinct pathways. Modulators from noncoding RNA, RNA-binding proteins, TFs, and kinases modulate the NF-jB/RelA activity with specific action modes consistent with their molecular functions and modulation level. The modulatory networks of NF-jB/RelA in the context epithelial-mesenchymal transition (EMT) and burn injury have different modulators, including those involved in extracellular matrix (FBN1), cytoskeletal regulation (ACTN1), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long intergenic nonprotein coding RNA, and tumor suppression (FOXP1) for EMT, and TXNIP, GAPDH, PKM2, IFIT5, LDHA, NID1, and TPP1 for burn injury.

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“…Maintenance of epithelial integrity is critical to normal cellular signaling, pulmonary homeostasis, and response to toxicants and allergen exposures. Moreover, this cell type plays a dynamic role in initiating innate signaling programs in response to physical, chemical and biological challenge through coordinating secretion of cytokines, defensins, and alarmins [2;3]. Injury, subsequent inflammation and the loss of epithelial basement membrane integrity also promote epithelial cell activation by extracellular matrix-associated factors.…”

Section: Introductionmentioning

confidence: 99%

“…Recently we have found that EMT also produces complex alterations in the tumor necrosis factor (TNF)α, signal transduction pathway [10]. The EMT state produces profound changes in TNFα signaling pathway coupling its canonical and noncanonical arms through transcriptional reprogramming of the TRAF1 and NFκB1 promoters [3;10]. As a result, the “coupling constant” e.g., the lag time between activation of the canonical and the noncanonical NF-κB program, was markedly reduced by EMT.…”

Section: Introductionmentioning

confidence: 99%

“…The “systems” concept relies on quantitative high throughput proteome measurements in response to external perturbation. This approach makes no a priori assumptions about the mechanisms underlying the response, allowing for the identification of new and less expected findings[3]. In this study, we develop a systems-level approach by perturbation of signaling programs in normal and EMT states followed by measurement of phospho-protein changes using enzyme-linked immunosorbent assays (ELISA) with bead-based microspheres[11].…”

Section: Introductionmentioning

confidence: 99%

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Mixed-effects model of epithelial–mesenchymal transition reveals rewiring of signaling networks

Desai

Yang

Tian

et al. 2015

Cellular Signalling

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The type II Epithelial-Mesenchymal Transition (EMT) produces airway fibrosis and remodeling, contributing to the severity of asthma and chronic obstructive pulmonary disease. While numerous studies have been done on the mechanisms of the transition itself, few studies have investigated the system effects of EMT on signaling networks. Here, we use mixed effects modeling to develop a computational model of phospho-protein signaling data that compares human small airway epithelial cells (hSAECs) with their EMT-transformed counterparts across a series of perturbations with 8 ligands and 5 inhibitors, revealing previously uncharacterized changes in signaling in the EMT state. Strong couplings between Menadione, TNFα and TGFβ and their known phospho-substrates were revealed after mixed effects modeling. Interestingly, the overall phospho-protein response was attenuated in EMT, with loss of Mena and TNFα coupling to heat shock protein (HSP)-27. These differences persisted after correction for EMT-induced changes in phospho-protein substrate abundance. Construction of network topology maps showed significant changes between the two cellular states, including a linkage between glycogen synthase kinase (GSK)-3α and small body size/ Mothers Against Decapentaplegic (SMAD)2. The model also predicted a loss of p38 mitogen activated protein kinase (p38MAPK)-independent HSP27 signaling, which we experimentally validated. We further characterized the relationship between HSP27 and signal transducers and activators of transcription (STAT)3 signaling, and determined that loss of HSP27 following EMT is only partially responsible for the downregulation of STAT3. These rewired connections represent therapeutic targets that could potentially reverse EMT and restore a normal phenotype to the respiratory mucosa.

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Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma

Cited by 103 publications

References 117 publications

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Inferring Genome-Wide Functional Modulatory Network: A Case Study on NF-κB/RelA Transcription Factor

Mixed-effects model of epithelial–mesenchymal transition reveals rewiring of signaling networks

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