scholarly journals Unstable FoxP3+ T regulatory cells in NZW mice

2016 ◽  
Vol 113 (5) ◽  
pp. 1345-1350 ◽  
Author(s):  
Fabien Dépis ◽  
Ho-Keun Kwon ◽  
Diane Mathis ◽  
Christophe Benoist
Keyword(s):  
T Regulatory Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Foxp3 Expression ◽  
Inbred Strains ◽  
Treg Cells ◽  
Special Focus ◽  
Signature Genes ◽  
Single Defect ◽  
Inbred Strains Of Mice

Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.

scholarly journals Phenotypic and clonal stability of antigen-inexperienced memory-like T cells across the genetic background, hygienic status, and aging

2020 ◽  
Author(s):  
Alena Moudra ◽  
Veronika Niederlova ◽  
Jiri Novotny ◽  
Lucie Schmiedova ◽  
Jan Kubovciak ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Genetic Background ◽  
Expression Profiles ◽  
Bacterial Colonization ◽  
Gene Expression Profiles ◽  
Inbred Strains ◽  
Microbial Colonization ◽  
Independent Manner ◽  
Different Genetic Background

AbstractAntigen-inexperienced memory-like T (AIMT) cells are functionally unique T cells representing one of the two largest subsets of murine CD8+ T cells. However, differences between laboratory inbred strains, insufficient data from germ-free mice, a complete lack of data from feral mice, and unclear relationship between AIMT cells formation during aging represent major barriers for better understanding of their biology. We performed a thorough characterization of AIMT cells from mice of different genetic background, age, and hygienic status by flow cytometry and multi-omics approaches including analyses of gene expression, TCR repertoire, and microbial colonization. Our data showed that AIMT cells are steadily present in mice independently of their genetic background and hygienic status. Despite differences in their gene expression profiles, young and aged AIMT cells originate from identical clones. We identified that CD122 discriminates two major subsets of AIMT cells in a strain-independent manner. Whereas thymic CD122LOW AIMT cells (innate memory) prevail only in young animals with high thymic IL-4 production, peripheral CD122HIGH AIMT cells (virtual memory) dominate in aged mice. Co-housing with feral mice changed the bacterial colonization of laboratory strains, but had only minimal effects on the CD8+ T-cell compartment including AIMT cells.

scholarly journals Homeobox protein Hhex negatively regulates Treg cells by inhibiting Foxp3 expression and function

2019 ◽  
Vol 116 (51) ◽  
pp. 25790-25799 ◽  
Author(s):  
Sung Woong Jang ◽  
Soo Seok Hwang ◽  
Hyeong Su Kim ◽  
Min Kyung Kim ◽  
Woo Ho Lee ◽  
...  
Keyword(s):  
Essential Role ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Negative Regulator ◽  
Delayed Type Hypersensitivity ◽  
Type I ◽  
Signature Genes ◽  
Homeobox Protein ◽  
The Stability ◽  
And Function

Regulatory T (Treg) cells play an essential role in maintaining immune homeostasis, but the suppressive function of Treg cells can be an obstacle in the treatment of cancer and chronic infectious diseases. Here, we identified the homeobox protein Hhex as a negative regulator of Treg cells. The expression of Hhex was lower in Treg cells than in conventional T (Tconv) cells. Hhex expression was repressed in Treg cells by TGF-β/Smad3 signaling. Retroviral overexpression of Hhex inhibited the differentiation of induced Treg (iTreg) cells and the stability of thymic Treg (tTreg) cells by significantly reducing Foxp3 expression. Moreover, Hhex-overexpressing Treg cells lost their immunosuppressive activity and failed to prevent colitis in a mouse model of inflammatory bowel disease (IBD).Hhexexpression was increased; however,Foxp3expression was decreased in Treg cells in a delayed-type hypersensitivity (DTH) reaction, a type I immune reaction. Hhex directly bound to the promoters ofFoxp3and other Treg signature genes, includingIl2raandCtla4, and repressed their transactivation. The homeodomain and N-terminal repression domain of Hhex were critical for inhibiting Foxp3 and other Treg signature genes. Thus, Hhex plays an essential role in inhibiting Treg cell differentiation and function via inhibition of Foxp3.

scholarly journals Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types

2018 ◽  
Vol 115 (45) ◽  
pp. E10672-E10681 ◽  
Author(s):  
Angela M. Magnuson ◽  
Evgeny Kiner ◽  
Ayla Ergun ◽  
Jun Seok Park ◽  
Natasha Asinovski ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Treg Cells ◽  
The Cancer Genome Atlas ◽  
Transcriptional Signature ◽  
Normal Tissues ◽  
Mouse Tumors ◽  
Tumor Stages ◽  
Genes Encoding ◽  
Tumor Types

FoxP3+T regulatory (Treg) cells are central elements of immunologic tolerance. They are abundant in many tumors, where they restrict potentially favorable antitumor responses. We used a three-pronged strategy to identify genes related to the presence and function of Tregs in the tumor microenvironment. Gene expression profiles were generated from tumor-infiltrating Tregs (TITRs) of both human and mouse tumors and were compared with those of Tregs of lymphoid organs or normal tissues from the same individuals. A computational deconvolution of whole-tumor datasets from the Cancer Genome Atlas (TCGA) was performed to identify transcripts specifically associated with Tregs across thousands of tumors from different stages and locations. We identified a set of TITR-differential transcripts with striking reproducibility between tumor types in mice, between mice and humans, and between different human patients spanning tumor stages. Many of the TITR-preferential transcripts were shared with “tissue Tregs” residing in nonlymphoid tissues, but a tumor-preferential segment could be identified. Many of these TITR signature transcripts were confirmed by mining of TCGA datasets, which also brought forth transcript modules likely representing the parenchymal attraction of, or response to, tumor Tregs. Importantly, the TITR signature included several genes encoding effective targets of tumor immunotherapy. A number of other targets were validated by CRISPR-based gene inactivation in mouse Tregs. These results confirm the validity of the signature, generating a wealth of leads for understanding the role of Tregs in tumor progression and identifying potential targets for cancer immunotherapy.

scholarly journals Gene expression profiles in rat brain disclose CNS signature genes and regional patterns of functional specialisation

BMC Genomics ◽  
2007 ◽  
Vol 8 (1) ◽  
pp. 94 ◽  
Author(s):  
Christine Stansberg ◽  
Audun Vik-Mo ◽  
Rita Holdhus ◽  
Harald Breilid ◽  
Boleslaw Srebro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Brain ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Regional Patterns ◽  
Signature Genes

scholarly journals Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease

2011 ◽  
Vol 208 (10) ◽  
pp. 2069-2081 ◽  
Author(s):  
Jeffrey VanValkenburgh ◽  
Diana I. Albu ◽  
Chandra Bapanpally ◽  
Sarah Casanova ◽  
Danielle Califano ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Critical Role ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Regulatory Cells ◽  
Genes Encoding ◽  
Inflammatory Bowel

Dysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced Treg cells (iTreg cells) after Tgf-β treatment of conventional CD4+ T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for Treg suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4+ T cells in response to Tgf-β and generation of iTreg cells.

Identification of gene sets and pathways associated with lactation performance in mice

2013 ◽  
Vol 45 (5) ◽  
pp. 171-181 ◽  
Author(s):  
Jerry Wei ◽  
Palaniappan Ramanathan ◽  
Ian C. Martin ◽  
Christopher Moran ◽  
Rosanne M. Taylor ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Functional Annotation ◽  
Animal Studies ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Inbred Strains ◽  
Significant Negative Correlation ◽  
Transgenic Animal ◽  
Receptor Interaction ◽  
Lactation Performance

Mammary transcriptome analyses across the lactation cycle and transgenic animal studies have identified candidate genes for mammogenesis, lactogenesis and involution; however, there is a lack of information on pathways that contribute to lactation performance. Previously we have shown significant differences in lactation performance, mammary gland histology, and gene expression profiles during lactation [lactation day 9 (L9)] between CBA/CaH (CBA) and the superior performing QSi5 strains of mice. In the present study, we compared these strains at midpregnancy [pregnancy day 12 (P12)] and utilized these data along with data from a 14th generation of intercross (AIL) to develop an integrative analysis of lactation performance. Additional analysis by quantitative reverse transcription PCR examined the correlation between expression profiles of lactation candidate genes and lactation performance across six inbred strains of mice. The analysis demonstrated that the mammary epithelial content per unit area was similar between CBA and QSi5 mice at P12, while differential expression was detected in 354 mammary genes (false discovery rate < 0.1). Gene ontology and functional annotation analyses showed that functional annotation terms associated with cell division and proliferation were the most enriched in the differentially expressed genes between these two strains at P12. Further analysis revealed that genes associated with neuroactive ligand-receptor interaction and calcium signaling pathways were significantly upregulated and positively correlated with lactation performance, while genes associated with cell cycle and DNA replication pathways were downregulated and positively correlated with lactation performance. There was also a significant negative correlation between Grb10 expression and lactation performance. In summary, using an integrative genomic approach we have identified key genes and pathways associated with lactation performance.

scholarly journals Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yehudit Hasin-Brumshtein ◽  
Arshad H Khan ◽  
Farhad Hormozdiari ◽  
Calvin Pan ◽  
Brian W Parks ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Genetic Regulation ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Valuable Insight ◽  
Phenotypic Variance ◽  
Inbred Strains Of Mice ◽  
Hybrid Mouse Diversity Panel ◽  
The Many

Previous studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL 'hotspots' associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provide a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation.

Transcriptome analysis reveals key signature genes involved in the oncogenesis of lung cancer

2020 ◽  
Vol 29 (4) ◽  
pp. 475-482
Author(s):  
Fanlu Meng ◽  
Linlin Zhang ◽  
Yaoyao Ren ◽  
Qing Ma
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Interaction Network ◽  
Functional Enrichment ◽  
Sequencing Platform ◽  
Signature Genes ◽  
Regulated Expression

Previous studies have suggested potential signature genes for lung cancer, however, due to factors such as sequencing platform, control, data selection and filtration conditions, the results of lung cancer-related gene expression analysis are quite different. Here, we performed a meta-analysis on existing lung cancer gene expression results to identify Meta-signature genes without noise. In this study, functional enrichment, protein-protein interaction network, the DAVID, String, TfactS, and transcription factor binding were performed based on the gene expression profiles of lung adenocarcinoma and non-small cell lung cancer deposited in the GEO database. As a result, a total of 574 differentially expressed genes (DEGs) affecting the pathogenesis of lung cancer were identified (207 up-regulated expression and 367 down-regulated expression in lung cancer tissues). A total of 5,093 interactions existed among the 507 (88.3%) proteins, and 10 Meta-signatures were identified: AURKA, CCNB1, KIF11, CCNA2, TOP2A, CENPF, KIF2C, TPX2, HMMR, and MAD2L1. The potential biological functions of Meta-signature DEGs were revealed. In summary, this study identified key genes involved in the process of lung cancer. Our results would help the developing of novel biomarkers for lung cancer.

scholarly journals The genomic and transcriptomic foundations of viviparous seed development in mangroves

2020 ◽  
Author(s):  
Hongmei Qiao ◽  
Xiaoxuan Zhou ◽  
Wenyue Su ◽  
Xing Zhao ◽  
Pengfei Jin ◽  
...  
Keyword(s):  
Seed Development ◽  
Storage Proteins ◽  
Expression Profiles ◽  
Major Gene ◽  
Gene Expression Profiles ◽  
Comparative Genomic ◽  
Mangrove Species ◽  
Precocious Germination ◽  
Signature Genes ◽  
Genetic Features

AbstractVivipary in plants refers to a specific seed development and reproductive strategy where seeds minimize the dormancy stage and germinate while still attached to their maternal plants. It is one of the most unique adaptive genetic features used by many mangrove species where elongated hypocotyls aid in quick root emergence to anchor the seedling in coastal intertidal wetlands. The genetic mechanisms behind mangrove vivipary, however, remain elusive. Using comparative genomic and transcriptomic technologies to investigate viviparous mangroves and their close inland relatives, we found that a full array of gene expression profiles were altered, including key plant hormone metabolic pathways, high expression of embryonic signature genes, and reduced production of proanthocyanidins and storage proteins. Along with these changes, a major gene regulating seed dormancy, Delay of Germination-1 (DOG1), is entirely missing or defunct within the entire linage of the four genera with true viviparous characteristics. These results suggest a systemic level change is required to warrant the genetic program of mangrove vivipary. Understanding of the molecular processes of vivipary could benefit the design of pregerminated propagules for forestation in harsh environments or prevent precocious germination of grain crops pre- and post-harvest.

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