Transcriptome analysis in acute GI GVHD reveals a unique signature in children and shared biology with pediatric IBD
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE215068 | GEO | 2023/04/01
REPOSITORIES: GEO
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Project description:Steroid-refractory gastrointestinal graft-versus-host disease (GI GVHD) is a major barrier to successful hematopoietic stem cell transplant (HSCT). Poor understanding of the pathophysiology of GI GVHD contributes to continued poor outcomes and high mortality rates. We therefore obtained rectosigmoidal mucosal biopsies from post-HSCT patients with GI GVHD and submitted them to RNA-sequencing in order to transcriptomally characterize GI GVHD. These were compared to patients undergoing endoscopy for routine clinical indications. Using single end, 50bp reads processed using Kallisto using genome annotations from Gencode v24 with transcripts per million as the output. We included 14,239 trancsripts in our analysis, where we compared GVHD vs non-GVHD with significance defined as FDR<0.05 and FC 1.5 using R package DESeq2. We identified 164 key genes, of which 141 were upregulated in GVHD, and were ontologically related to microbial response, key immune effectors, and cell migration/chemotaxis. Down-regulated genes were related to nutrient metabolism. Additionally, we performed WGCNA that highlighted ERK as a key upregulated pathway in GI GVHD.
2022-03-07 | GSE168116 | GEO
Project description:Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft versus host disease (GVHD). CD4+ T cells that produce GM-CSF have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if there exists a unique CD4+ GM-CSF+ subset that differs from other defined T helper (TH) subtypes. Using single cell RNA sequencing analysis, we identified two CD4+ GM-CSF+ T cell populations that arose during GVHD and were distinguishable by the presence or absence of IFN-γ co-expression. CD4+ GM-CSF+ IFN-γ- T cells which emerged preferentially in the colon had a distinct transcriptional profile, employed unique gene regulatory networks, and possessed a non-overlapping TCR repertoire when compared to CD4+ GM-CSF+ IFN-γ+ T cells as well as all other transcriptionally defined CD4+ T cell populations in the colon. Functionally, this CD4+ GM-CSF+ T cell population contributed to pathological damage in the GI tract which was critically dependent upon signaling through the IL-7 receptor but was independent of type 1 interferon signaling. Thus, these studies help to unravel heterogeneity within CD4+ GM-CSF+ T cells that arise during GVHD and define a developmentally distinct colitogenic TH GM-CSF+ subset that mediates immunopathology.
2022-01-14 | GSE193475 | GEO
Project description:Plants monitor and integrate temperature, photoperiod and light quality signals to respond to continuous changes in their environment. The GIGANTEA (GI) protein is central in diverse signaling pathways, including photoperiodic, sugar and light signaling pathways, stress responses and circadian clock regulation. Previously, GI was shown to activate expression of the key floral regulators CONSTANS (CO) and FLOWERING LOCUS T (FT) by facilitating degradation of a family of CYCLING DOF FACTOR (CDF) transcriptional repressors. However, whether CDFs are implicated in other processes regulated by GI remains unclear. We investigated the contribution of the GI-CDF module to traits that depend on GI. Transcriptome profiling indicated that mutations in GI and the CDFs have antagonistic effects on expression of a wider set of genes than CO and FT, whilst other genes are regulated by GI independently of the CDFs. Detailed expression studies followed by phenotypic assays showed that the CDFs function downstream of GI to control responses to freezing temperatures and growth, but are not necessary for proper clock function. Thus GI-mediated regulation of CDFs contributes to several processes in addition to flowering, but is not implicated in all of the phenotypes influenced by GI. Seedlings of Col-0, the cdf1-R cdf2-1 cdf3-1 cdf5-1 quadruple mutant, gi-100 and gi-100 cdf1-R cdf2-1 cdf3-1 cdf5-1 quintuple mutant were grown for 10 days under LD conditions (16h light/8h dark). The aerial part of the seedlings was collected at ZT12 and RNA was prepared from three biological replicas
2015-07-31 | E-GEOD-59996 | biostudies-arrayexpress
Project description:BACKGROUND - IL-6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem cell transplantation (alloSCT) and is an attractive therapeutic target. METHODS - A registered phase I/II study (ACTRN12612000726853) of IL-6 receptor (IL-6R) neutralizing antibody administration on day -1 to patients receiving full or reduced-intensity conditioning (RIC) and alloSCT from HLA-matched sibling or unrelated donors with standard cyclosporin and methotrexate GVHD prophylaxis. The primary endpoint was incidence of grade II-IV acute GVHD. Outcomes were compared to a non-randomized but contemporaneous group of study patients receiving the same alloSCT in the absence of IL-6R mAb. FINDINGS - Cytokine and pharmacokinetic analysis confirmed transient IL-6 dysregulation in the first month after alloSCT with complete inhibition following IL-6R mAb administration. With median follow up of 497 days, the incidence of grade II-IV GVHD was 12.5% in recipients of IL-6R inhibition (n = 48) versus 41.5% in the (n = 53) control cohort (P = 0.001). Low rates of acute GVHD were noted in patients receiving IL-6R inhibition relative to control patients following both myeloablative (12.5% vs. 46.4%, P = 0.03) and RIC (12.5% vs. 36.0%, P = 0.04). The incidence of severe (grade III/IV) acute GVHD was 4.2% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.012). Relapse and chronic GVHD were unchanged. Immune reconstitution was preserved in recipients of IL-6R inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION - IL-6 is the principal detectable and dysregulated cytokine secreted after alloSCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution and a sustained graft-versus-leukemia effect. Single colour, Illumina Human HT12v4 Beadarrays.
2014-09-09 | E-GEOD-61201 | biostudies-arrayexpress
Project description:Plants monitor and integrate temperature, photoperiod and light quality signals to respond to continuous changes in their environment. The GIGANTEA (GI) protein is central in diverse signaling pathways, including photoperiodic, sugar and light signaling pathways, stress responses and circadian clock regulation. Previously, GI was shown to activate expression of the key floral regulators CONSTANS (CO) and FLOWERING LOCUS T (FT) by facilitating degradation of a family of CYCLING DOF FACTOR (CDF) transcriptional repressors. However, whether CDFs are implicated in other processes regulated by GI remains unclear. We investigated the contribution of the GI-CDF module to traits that depend on GI. Transcriptome profiling indicated that mutations in GI and the CDFs have antagonistic effects on expression of a wider set of genes than CO and FT, whilst other genes are regulated by GI independently of the CDFs. Detailed expression studies followed by phenotypic assays showed that the CDFs function downstream of GI to control responses to freezing temperatures and growth, but are not necessary for proper clock function. Thus GI-mediated regulation of CDFs contributes to several processes in addition to flowering, but is not implicated in all of the phenotypes influenced by GI.
2015-07-31 | GSE59996 | GEO
Project description:GIGANTEA (GI) is an important modulator of plant circadian system. Recent studies have reported that protein GI is localized in both nucleus and cytosol, and nuclear and cytosolic GI exert differential effect on plant circadian clock. We first generated GI-null mutants and transgenic Arabidopsis plants that expressed GI fused to green fluorescent protein gene (GIpro::GI-GFP) and GI-GFP with a nuclear localization signal (GIpro::GI-GFP-NLS) or with a nuclear export signal (GIpro::GI-GFP-NES) under the control of native promoter in GI-null mutants. To investigate differential roles of nuclear and cytosolic GI in regulating plant circadian clock, we performed genome-wide gene expression profiling for wild-type plants and the GI-transgenic plants at morning and evening, and analyzed complementation patterns of gi-2 lesion by nuclear and cytosolic GI. As a result, we identified four complementation patterns representing genes affected by only nuclear GI (GIN) or cytosolic GI (GIC), those by either GIN or GIC, and those by the action of both GIN and GIC. Furthermore, we compared the transgenic plants expressing GIpro::GI-GFP with WT and the other GI-transgenic plants to confirm whether abnormally expressed genes by the gi-2 mutation can be complemented by restoring protein GI. Wild-type plants (Col), GI-null mutants (gi-2), and the other transgenic gi-2 plants expressing GIpro::GI-GFP (called GI plants), GIpro::GI-GFP-NLS (called GI-NLS plants), and GIpro::GI-GFP-NES (called GI-NES plants) were grown for seven days under conditions of 16 h light and 8 h dark (LD) and harvested at 1h (ZT1) and 16 hr (ZT16) after the light is turned on, representing morning and evening, respectively. mRNA levels were measured from three biological replicates of Col, gi-2, GI-NLS, GI-NES, and GI.
2013-09-01 | E-GEOD-47169 | biostudies-arrayexpress
Project description:We report the expression of microbial metabolite tranporters in mucosal biopsies from children with GVHD
2018-08-01 | GSE102228 | GEO
Project description:GIGANTEA (GI) is an important modulator of plant circadian system. Recent studies have reported that protein GI is localized in both nucleus and cytosol, and nuclear and cytosolic GI exert differential effect on plant circadian clock. We first generated GI-null mutants and transgenic Arabidopsis plants that expressed GI fused to green fluorescent protein gene (GIpro::GI-GFP) and GI-GFP with a nuclear localization signal (GIpro::GI-GFP-NLS) or with a nuclear export signal (GIpro::GI-GFP-NES) under the control of native promoter in GI-null mutants. To investigate differential roles of nuclear and cytosolic GI in regulating plant circadian clock, we performed genome-wide gene expression profiling for wild-type plants and the GI-transgenic plants at morning and evening, and analyzed complementation patterns of gi-2 lesion by nuclear and cytosolic GI. As a result, we identified four complementation patterns representing genes affected by only nuclear GI (GIN) or cytosolic GI (GIC), those by either GIN or GIC, and those by the action of both GIN and GIC. Furthermore, we compared the transgenic plants expressing GIpro::GI-GFP with WT and the other GI-transgenic plants to confirm whether abnormally expressed genes by the gi-2 mutation can be complemented by restoring protein GI.
2013-09-01 | GSE47169 | GEO
Project description:Using an experimental model of graft versus host disease (GVHD) to examine T cell-mediated inflammation within the colon, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin, CD11c, has a biased central memory phenotype and memory T cell transcriptional profile, possesses innate-like properties by gene expression analysis, and has increased expression of the gut-homing molecules, α4β7 and CCR9. Using a number of complementary GVHD mouse models, we show that adoptive transfer of these cells results in TH1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality due to early accumulation of these cells in the GI tract. The pathogenic effects of this CD4+ T cell population was critically dependent upon co-expression of the IL-23 receptor which was required for maximal inflammatory effects. Colonic inflammation was regulated by IL-10 that was produced by non-Foxp3-expressing CD4+ T cells which attenuated lethality in the absence of functional CD4+ Foxp3+ T cells. Thus, coordinate expression of CD11c and the IL-23R defines a novel IL-10 regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers as occurs in GVHD as well as other immune-mediated inflammatory bowel disorders.
2016-08-12 | GSE83552 | GEO