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Open accessJournal ArticleDOI: 10.1038/S41590-021-00889-2

Wnt-β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression.

04 Mar 2021-Nature Immunology (Nature Publishing Group)-Vol. 22, Iss: 4, pp 471-484
Abstract: The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of β-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-β-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt-β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of β-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.

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Topics: FOXP3 (56%), RAR-related orphan receptor gamma (53%), Wnt signaling pathway (51%) ... show more
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8 results found


Journal ArticleDOI: 10.1038/S41590-021-00987-1
Abu Osman1, Bingyu Yan2, Ying Li1, Kevin D. Pavelko1  +6 moreInstitutions (3)
12 Aug 2021-Nature Immunology
Abstract: The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.

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Topics: T cell (67%), Cytotoxic T cell (63%), FOXP3 (60%) ... show more

2 Citations


Open accessJournal ArticleDOI: 10.3389/FIMMU.2021.694833
Daniel DiToro1, Rajatava Basu2Institutions (2)
Abstract: The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.

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Topics: T helper cell (58%), T cell (57%), Immune system (52%)

1 Citations


Open accessJournal ArticleDOI: 10.3389/FIMMU.2021.717421
Abstract: Regulatory T-cells (Tregs) are important for maintaining self-tolerance and tissue homeostasis. The functional plasticity of Tregs is a key feature of this lineage, as it allows them to adapt to different microenvironments, adopt transcriptional programs reflective of their environments and tailor their suppressive capacity in a context-dependent fashion. Tregs, particularly effector Tregs (eTregs), are abundant in many types of tumors. However, the functional and transcriptional plasticity of eTregs in tumors remain largely to be explored. Although depletion or inhibition of systemic Tregs can enhance anti-tumor responses, autoimmune sequelae have diminished the enthusiasm for such approaches. A more effective approach should specifically target intratumoral Tregs or subvert local Treg-mediated suppression. This mini-review will discuss the reported mechanisms by which the stability and suppressive function of tumoral Tregs are modulated, with the focus on eTregs and a subset of eTregs, follicular regulatory T (TFR) cells, and how to harness this knowledge for the future development of new effective cancer immunotherapies that selectively target the tumor local response while sparing the systemic side effects.

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Topics: FOXP3 (54%), Tissue homeostasis (53%)

1 Citations


Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.755768
Abstract: Mastitis is a worldwide production disease in dairy cows, which mainly affects milk yield, causing huge economic losses to dairy farmers. Lentinan is a kind of polysaccharide extracted from Lentinus edodes, which has no toxicity and possesses various pharmacological activities including antibacterial and immunomodulatory effects. Therefore, the anti-inflammatory function of lentinan on LPS-stimulated mastitis was carried out, and the mechanism involved was explored. In vivo, lentinan greatly reduced LPS-stimulated pathological injury, myeloperoxidase (MPO) activity, and the proinflammatory factor production (TNF-α and IL-1β) in mice. Further study was performed to determine the activation of the Wnt/β-catenin pathway during LPS stimulation. These results suggested that LPS-induced activation of the Wnt/β-catenin pathway was suppressed by lentinan administration. In vitro, we observed that the mouse mammary epithelial cell (mMEC) viability was not affected by lentinan treatment. As expected, LPS increased the TNF-α and IL-1β protein secretion and the activation of the Wnt/β-catenin pathway that was inhibited by lentinan administration in a dose-dependent manner in mMECs. Conclusively, lentinan exerts the anti-inflammatory function in LPS-stimulated mastitis via inhibiting the activation of the Wnt/β-catenin pathway. Thus, the results of our study also gave an insight that lentinan may serve as a potential treatment for mastitis.

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Topics: Lentinan (75%)

Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.772101
Abstract: Increased risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients has been attributed to long-standing chronic inflammation, with the contribution of genetic alterations and environmental factors such as the microbiota. Moreover, accumulating data indicate that IBD-associated CRC (IBD-CRC) may initiate and develop through a pathway of tumorigenesis distinct from that of sporadic CRC. This mini-review summarizes the current knowledge of IBD-CRC, focusing on the main mechanisms underlying its pathogenesis, and on the important role of immunomodulators and biologics used to treat IBD patients in interfering with the inflammatory process involved in carcinogenesis.

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69 results found


Open accessJournal ArticleDOI: 10.1073/PNAS.0506580102
Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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26,320 Citations


Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP616
01 Jan 2010-Bioinformatics
Abstract: Summary: It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data. Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org).

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Topics: Bioconductor (64%)

21,575 Citations


Open accessJournal ArticleDOI: 10.1093/NAR/28.1.27
Minoru Kanehisa1, Susumu Goto1Institutions (1)
Abstract: Kyoto Encyclopedia of Genes and Genomes (KEGG) is a knowledge base for systematic analysis of gene functions in terms of the networks of genes and molecules. The major component of KEGG is the PATHWAY database that consists of graphical diagrams of biochemical pathways including most of the known metabolic pathways and some of the known regulatory pathways. The pathway information is also represented by the ortholog group tables summarizing orthologous and paralogous gene groups among different organisms. KEGG maintains the GENES database for the gene catalogs of all organisms with complete genomes and selected organisms with partial genomes, which are continuously re-annotated, as well as the LIGAND database for chemical compounds and enzymes. Each gene catalog is associated with the graphical genome map for chromosomal locations that is represented by Java applet. In addition to the data collection efforts, KEGG develops and provides various computational tools, such as for reconstructing biochemical pathways from the complete genome sequence and for predicting gene regulatory networks from the gene expression profiles. The KEGG databases are daily updated and made freely available (http://www.genome.ad.jp/kegg/).

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Topics: KEGG (70%), Paralogous Gene (53%), Genome (53%) ... show more

19,643 Citations


Open accessJournal ArticleDOI: 10.18637/JSS.V033.I01
Abstract: We develop fast algorithms for estimation of generalized linear models with convex penalties. The models include linear regression, two-class logistic regression, and multinomial regression problems while the penalties include l(1) (the lasso), l(2) (ridge regression) and mixtures of the two (the elastic net). The algorithms use cyclical coordinate descent, computed along a regularization path. The methods can handle large problems and can also deal efficiently with sparse features. In comparative timings we find that the new algorithms are considerably faster than competing methods.

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Topics: Elastic net regularization (70%), Generalized iterative scaling (65%), Coordinate descent (61%) ... show more

10,799 Citations


Open accessJournal ArticleDOI: 10.1186/GB-2008-9-9-R137
Yong Zhang1, Tao Liu1, Clifford A. Meyer1, Jérôme Eeckhoute2  +8 moreInstitutions (5)
17 Sep 2008-Genome Biology
Abstract: We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

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Topics: Peak calling (54%), Chromatin binding (51%)

9,966 Citations