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Garrett-Sinha LA. An update on the roles of transcription factor Ets1 in autoimmune diseases. WIREs Mech Dis 2023; 15:e1627. [PMID: 37565573 PMCID: PMC10842644 DOI: 10.1002/wsbm.1627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/12/2023]
Abstract
Transcription factors are crucial to regulate gene expression in immune cells and in other cell types. In lymphocytes, there are a large number of different transcription factors that are known to contribute to cell differentiation and the balance between quiescence and activation. One such transcription factor is E26 oncogene homolog 1 (Ets1). Ets1 expression is high in quiescent B and T lymphocytes and its levels are decreased upon activation. The human ETS1 gene has been identified as a susceptibility locus for many autoimmune and inflammatory diseases. In accord with this, gene knockout of Ets1 in mice leads to development of a lupus-like autoimmune disease, with enhanced activation and differentiation of both B cells and T cells. Prior reviews have summarized functional roles for Ets1 based on studies of Ets1 knockout mice. In recent years, numerous additional studies have been published that further validate ETS1 as a susceptibility locus for human diseases where immune dysregulation plays a causative role. In this update, new information that further links Ets1 to human autoimmune diseases is organized and collated to serve as a resource. This update also describes recent studies that seek to understand molecularly how Ets1 regulates immune cell activation, either using human cells and tissues or mouse models. This resource is expected to be useful to investigators seeking to understand how Ets1 may regulate the human immune response, particularly in terms of its roles in autoimmunity and inflammation. This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Lee Ann Garrett-Sinha
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA
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COVID-19 and Inflammatory Bowel Diseases: Risk Assessment, Shared Molecular Pathways, and Therapeutic Challenges. Gastroenterol Res Pract 2020; 2020:1918035. [PMID: 32714386 PMCID: PMC7352130 DOI: 10.1155/2020/1918035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 06/29/2020] [Indexed: 12/20/2022] Open
Abstract
Background The novel coronavirus SARS-CoV-2 causing COVID-19 disease is yielding a global outbreak with severe threats to public health. In this paper, we aimed at reviewing the current knowledge about COVID-19 infectious risk status in inflammatory bowel disease (IBD) patients requiring immunosuppressive medication. We also focused on several molecular insights that could explain why IBD patients appear not to have higher risks of infection and worse outcomes in COVID-19 than the general population in an attempt to provide scientific support for safer decisions in IBD patient care. Methods PubMed electronic database was interrogated for relevant articles involving data about common molecular pathways and shared treatment strategies between SARS-CoV-2, SARS-CoV-1, MERS-CoV, and inflammatory bowel diseases. Besides, Neural Covidex, an artificial intelligence tool, was used to answer queries about pathogenic coronaviruses and possible IBD interactions using the COVID-19 Open Research Dataset (CORD-19). Discussions. Few molecular and therapeutic interactions between IBD and pathogenic coronaviruses were explored. First, we showed how the activity of soluble angiotensin-converting enzyme 2, CD209L other receptors, and phosphorylated α subunit of eukaryotic translation initiation factor 2 might exert protective impact in IBD in case of coronavirus infection. Second, IBD medication was discussed in the context of possible beneficial effects on COVID-19 pathogeny, including “cytokine storm” prevention and treatment, immunomodulation, interferon signaling blocking, and viral endocytosis inhibition. Conclusions Using the current understanding of SARS-CoV-2 as well as other pathogenic coronaviruses immunopathology, we showed why IBD patients should not be considered at an increased risk of infection or more severe outcomes. Whether our findings are entirely applicable to the pathogenesis, disease susceptibility, and treatment management of SARS-CoV-2 infection in IBD must be further explored.
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Machine Learning-Based Gene Prioritization Identifies Novel Candidate Risk Genes for Inflammatory Bowel Disease. Inflamm Bowel Dis 2017; 23:1516-1523. [PMID: 28795970 DOI: 10.1097/mib.0000000000001222] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders, associated with genetic, immunologic, and environmental factors. Although hundreds of genes are implicated in IBD etiology, it is likely that additional genes play a role in the disease process. We developed a machine learning-based gene prioritization method to identify novel IBD-risk genes. METHODS Known IBD genes were collected from genome-wide association studies and annotated with expression and pathway information. Using these genes, a model was trained to identify IBD-risk genes. A comprehensive list of 16,390 genes was then scored and classified. RESULTS Immune and inflammatory responses, as well as pathways such as cell adhesion, cytokine-cytokine receptor interaction, and sulfur metabolism were identified to be related to IBD. Scores predicted for IBD genes were significantly higher than those for non-IBD genes (P < 10). There was a significant association between the score and having an IBD publication (P < 10). Overall, 347 genes had a high prediction score (>0.8). A literature review of the genes, excluding those used to train the model, identified 67 genes without any publication concerning IBD. These genes represent novel candidate IBD-risk genes, which can be targeted in future studies. CONCLUSIONS Our method successfully differentiated IBD-risk genes from non-IBD genes by using information from expression data and a multitude of gene annotations. Crucial features were defined, and we were able to detect novel candidate risk genes for IBD. These findings may help detect new IBD-risk genes and improve the understanding of IBD pathogenesis.
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Al-toma A, Nijeboer P, Bouma G, Visser O, Mulder CJJ. Hematopoietic stem cell transplantation for non-malignant gastrointestinal diseases. World J Gastroenterol 2014; 20:17368-17375. [PMID: 25516648 PMCID: PMC4265595 DOI: 10.3748/wjg.v20.i46.17368] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 04/30/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
Both, autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used to cure or ameliorate a variety of malignant and non-malignant diseases. The rationale behind this strategy is based on the concept of immunoablation using high-dose chemotherapy, with subsequent regeneration of naive T-lymphocytes derived from reinfused hematopoietic progenitor cells. In addition, the use of HSCT allows for the administration of high-dose chemotherapy (whether or not combined with immunomodulating agents such as antithymocyte globulin) resulting in a prompt remission in therapy-refractory patients. This review gives an update of the major areas of successful uses of HSCT in non-malignant gastrointestinal disorders. A Medline search has been conducted and all relevant published data were analyzed. HSCT has been proved successful in treating refractory Crohn’s disease (CD). Patients with refractory celiac disease type II and a high risk of developing enteropathy associated T-cell lymphoma have shown promising improvement. Data concerning HSCT and mesenchymal SCT in end-stage chronic liver diseases are encouraging. In refractory autoimmune gastrointestinal diseases high-dose chemotherapy followed by HSCT seems feasible and safe and might result in long-term improvement of disease activity. Mesenchymal SCT for a selected group of CD is promising and may represent a significant therapeutic alternative in treating fistulas in CD.
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Chapard C, Hohl D, Huber M. The role of the TRAF-interacting protein in proliferation and differentiation. Exp Dermatol 2012; 21:321-6. [PMID: 22509826 DOI: 10.1111/j.1600-0625.2012.01477.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. Addition of ubiquitin moieties to proteins is carried out by the sequential action of three enzymes: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; and E3, ubiquitin ligase. The TRAF-interacting protein (TRAIP, TRIP, RNF206) functions as Really Interesting New Gene (RING)-type E3 ubiquitin ligase, but its physiological substrates are not yet known. TRAIP was reported to interact with TRAF [tumor necrosis factor (TNF) receptor-associated factors] and the two tumor suppressors CYLD and Syk (spleen tyrosine kinase). Ectopically expressed TRAIP was shown to inhibit nuclear factor-kappa B (NF-κB) signalling. However, recent results suggested a role for TRAIP in biological processes other than NF-κB regulation. Knock-down of TRAIP in human epidermal keratinocytes repressed cellular proliferation and induced a block in the G1/S phase of the cell cycle without affecting NF-κB signalling. TRAIP is necessary for embryonal development as mutations affecting the Drosophila homologue of TRAIP are maternal effect-lethal mutants, and TRAIP knock-out mice die in utero because of aberrant regulation of cell proliferation and apoptosis. These findings underline the tight link between TRAIP and cell proliferation. In this review, we summarize the data on TRAIP and put them into a larger perspective regarding the role of TRAIP in the control of tissue homeostasis.
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Affiliation(s)
- Christophe Chapard
- Service of Dermatology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
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Differential regulation of peripheral leukocyte genes in patients with active Crohn's disease and Crohn's disease in remission. J Clin Gastroenterol 2010; 44:120-6. [PMID: 19826276 DOI: 10.1097/mcg.0b013e3181a9ef53] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
GOALS Assessment of disease severity is a frequent challenge in the management of Crohn's disease. Noninvasive, accurate markers for monitoring disease activity are urgently required. Specific gene expression patterns and molecular biomarkers associated with active Crohn's disease could serve as such markers, thereby providing a novel approach to disease activity monitoring. BACKGROUND Gene expression profiling in circulating leukocytes has shown promise in several medical conditions and blood may provide an easily accessible surrogate tissue for using gene expression profiling to assess activity of Crohn's disease. STUDY In this study, we compared genome-wide transcription profiles of circulating leukocytes in patients with active and quiescent Crohn's disease. RESULTS We observed complex changes in blood gene expression patterns in active Crohn's disease: genes of various functional categories were differentially regulated between active and inactive Crohn's disease. We specifically identified a number of inflammatory molecules overexpressed or underexpressed in active Crohn's disease and validated a subset of these genes by real-time reverse transcription-polymerase chain reaction. CONCLUSIONS The genes differentially regulated in peripheral leukocytes represent potential new biomarkers for assessing the activity of Crohn's disease.
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Abstract
Technological advances in genomics and transcriptomics have resulted in the introduction of molecular tests into the clinical arena. Despite established uses of such tests in the oncology field, their integration into the management of complex diseases has not been widely evaluated. Progress in the field of inflammatory bowel disease (IBD) genetics has been rapid in recent years, and these advances have provided more urgent impetus to investigating the role of molecular tests in IBD. This article summarizes the current state of molecular testing available for IBD, and the potential utility of such tests as research in the area widens.
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Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med 2009; 206:1883-97. [PMID: 19652016 PMCID: PMC2737162 DOI: 10.1084/jem.20091233] [Citation(s) in RCA: 337] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2009] [Accepted: 07/08/2009] [Indexed: 12/12/2022] Open
Abstract
The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of (111)In-labeled neutrophils at these sites and clearance of (32)P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.
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Affiliation(s)
- Andrew M. Smith
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Farooq Z. Rahman
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Bu'Hussain Hayee
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Simon J. Graham
- Molecular and Cellular Technologies, Molecular Discovery Research, GSK, Harlow, Essex CM19 5AW, England, UK
| | - Daniel J.B. Marks
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Gavin W. Sewell
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Christine D. Palmer
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Jonathan Wilde
- Molecular and Cellular Technologies, Molecular Discovery Research, GSK, Harlow, Essex CM19 5AW, England, UK
| | - Brian M.J. Foxwell
- Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, England, UK
| | - Israel S. Gloger
- Molecular and Cellular Technologies, Molecular Discovery Research, GSK, Harlow, Essex CM19 5AW, England, UK
| | - Trevor Sweeting
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Mark Marsh
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Ann P. Walker
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
| | - Stuart L. Bloom
- Department of Gastroenterology, University College London Hospital, London NW1 2BU, England UK
| | - Anthony W. Segal
- Department of Medicine, Department of Statistical Science, and Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, England, UK
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Jedlicka P, Gutierrez-Hartmann A. Ets transcription factors in intestinal morphogenesis, homeostasis and disease. Histol Histopathol 2008; 23:1417-24. [PMID: 18785124 PMCID: PMC2716142 DOI: 10.14670/hh-23.1417] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Ets transcription factors comprise a large family of sequence-specific regulators of gene expression with important and diverse roles in development and disease. Most Ets family members are expressed in the developing and/or mature intestine, frequently in a compartment-specific and temporally dynamic manner. However, with the exception of the highly expressed Elf3, involved in embryonic epithelial differentiation, little is known about Ets functions in intestinal development and homeostasis. Ets factors show altered expression in colon cancer, where they regulate pathways relevant to tumor progression. Ets factors also likely act as important modifiers of non-neoplastic intestinal disease by regulating pathways relevant to tissue injury and repair. Despite a large body of published work on Ets biology, much remains to be learned about the precise functions of this large and diverse gene family in intestinal morphogenesis, homeostasis, and both neoplastic and non-neoplastic pathology.
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Affiliation(s)
- Paul Jedlicka
- Department of Pathology, University of Colorado Denver, Aurora CO 80045, USA.
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