Gene Expression Nebulas
4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma.
Kim HD, Park S, Jeong S, Lee YJ, Lee H, Kim CG, Kim KH, Hong SM, Lee JY, Kim S, Kim HK, Min BS, Chang JH, Ju YS, Shin EC, Song GW, Hwang S, Park SH.
Hepatology (Baltimore, Md.). 71(3). 2019-10-18
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Abstract
Background and aimsTargeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8+ T cells (CD8+ tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC).Approach and resultsTumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8+ TILs. 4-1BB expression was almost exclusively detected on CD8+ T cells in the tumor-especially on programmed death 1 (PD-1)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high CD8+ TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T-cell activation.Conclusion4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation. |
A conserved transcriptional response to intranasal Ebola virus exposure in nonhuman primates prior to onset of fever.
Speranza E, Bixler SL, Altamura LA, Arnold CE, Pratt WD, Taylor-Howell C, Burrows C, Aguilar W, Rossi F, Shamblin JD, Wollen SE, Zelko JM, Minogue T, Nagle E, Palacios G, Goff AJ, Connor JH.
Science translational medicine. 10(434). 2018-03-01
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Abstract
Ebola virus disease (EVD), caused by Ebola virus (EBOV), is a severe illness characterized by case fatality rates of up to 90%. The sporadic nature of outbreaks in resource-limited areas has hindered the ability to characterize the pathogenesis of EVD at all stages of infection but particularly early host responses. Pathogenesis is often studied in nonhuman primate (NHP) models of disease that replicate major aspects of human EVD. Typically, NHP models use a large infectious dose, are carried out through intramuscular or aerosol exposure, and have a fairly uniform disease course. By contrast, we report our analysis of the host response to EBOV after intranasal exposure. Twelve cynomolgus macaques were infected with 100 plaque-forming units of EBOV/Makona through intranasal exposure and presented with varying times to onset of EVD. We used RNA sequencing and a newly developed NanoString CodeSet to monitor the host response via changes in RNA transcripts over time. When individual animal gene expression data were phased based on the onset of sustained fever, the first clinical sign of severe disease, mathematical models indicated that interferon-stimulated genes appeared as early as 4 days before fever onset. This demonstrates that lethal EVD has a uniform and predictable response to infection regardless of time to onset. Furthermore, expression of a subset of genes could predict disease development before other host-based indications of infection such as fever.
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A Core Regulatory Pathway Controlling Rice Tiller Angle Mediated by the LAZY1-Dependent Asymmetric Distribution of Auxin.
Zhang N, Yu H, Yu H, Cai Y, Huang L, Xu C, Xiong G, Meng X, Wang J, Chen H, Liu G, Jing Y, Yuan Y, Liang Y, Li S, Smith SM, Li J, Wang Y.
The Plant cell. 30(7). 2018-06-18
Corresponding Author Information
Yonghong Wang: State Key Laboratory of Plant Genomics and National Center for Plant Gene Research (Beijing), Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100039, China; CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Abstract
Tiller angle in cereals is a key shoot architecture trait that strongly influences grain yield. Studies in rice (Oryza sativa) have implicated shoot gravitropism in the regulation of tiller angle. However, the functional link between shoot gravitropism and tiller angle is unknown. Here, we conducted a large-scale transcriptome analysis of rice shoots in response to gravistimulation and identified two new nodes of a shoot gravitropism regulatory gene network that also controls rice tiller angle. We demonstrate that HEAT STRESS TRANSCRIPTION FACTOR 2D (HSFA2D) is an upstream positive regulator of the LAZY1-mediated asymmetric auxin distribution pathway. We also show that two functionally redundant transcription factor genes, WUSCHEL RELATED HOMEOBOX6 (WOX6) and WOX11, are expressed asymmetrically in response to auxin to connect gravitropism responses with the control of rice tiller angle. These findings define upstream and downstream genetic components that link shoot gravitropism, asymmetric auxin distribution, and rice tiller angle. The results highlight the power of the high-temporal-resolution RNA-seq data set and its use to explore further genetic components controlling tiller angle. Collectively, these approaches will identify genes to improve grain yields by facilitating the optimization of plant architecture.
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A distinct epigenetic profile distinguishes stenotic from non-inflamed fibroblasts in the ileal mucosa of Crohn's disease patients.
Li Yim AYF, de Bruyn JR, Duijvis NW, Sharp C, Ferrero E, de Jonge WJ, Wildenberg ME, Mannens MMAM, Buskens CJ, D'Haens GR, Henneman P, Te Velde AA.
PloS one. 13(12). 2018-12-27
Corresponding Author Information
Anje A. te Velde: Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Abstract
BackgroundThe chronic remitting and relapsing intestinal inflammation characteristic of Crohn's disease frequently leads to fibrosis and subsequent stenosis of the inflamed region. Approximately a third of all Crohn's disease patients require resection at some stage in their disease course. As the pathogenesis of Crohn's disease associated fibrosis is largely unknown, a strong necessity exists to better understand the pathophysiology thereof.MethodsIn this study, we investigated changes of the DNA methylome and transcriptome of ileum-derived fibroblasts associated to the occurrence of Crohn's disease associated fibrosis. Eighteen samples were included in a DNA methylation array and twenty-one samples were used for RNA sequencing.ResultsMost differentially methylated regions and differentially expressed genes were observed when comparing stenotic with non-inflamed samples. By contrast, few differences were observed when comparing Crohn's disease with non-Crohn's disease, or inflamed with non-inflamed tissue. Integrative methylation and gene expression analyses revealed dysregulation of genes associated to the PRKACA and E2F1 network, which is involved in cell cycle progression, angiogenesis, epithelial to mesenchymal transition, and bile metabolism.ConclusionOur research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts. |
A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.
Liang Y, Tsoi LC, Xing X, Beamer MA, Swindell WR, Sarkar MK, Berthier CC, Stuart PE, Harms PW, Nair RP, Elder JT, Voorhees JJ, Kahlenberg JM, Gudjonsson JE.
Nature immunology. 18(2). 2016-12-19
Corresponding Author Information
Kathrin Plath: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Abstract
Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjögren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development.
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