*MMP1* bimodal expression and differential response to inflammatory mediators is linked to promoter polymorphisms
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE23070 | GEO | 2011/07/20
SECONDARY ACCESSION(S): PRJNA131673
REPOSITORIES: GEO
Similar Datasets
Project description:Identifying the functional importance of the millions of single nucleotide polymorphisms (SNPs) in the human genome is a difficult challenge. Therefore, a reverse strategy, which identifies functionally important SNPs by virtue of the bimodal abundance across the human population of the SNP-related mRNAs will be useful. Those mRNA transcripts that are expressed at two distinct abundances in proportion to SNP allele frequency may warrant further study. Matrix metalloproteinase 1 (MMP1) is important in both normal development and in numerous pathologies. Although much research has been conducted to investigate the expression of MMP1 in many different cell types and conditions, the regulation of its expression is still not fully understood.In this study, we used a novel but straightforward method based on agglomerative hierarchical clustering to identify bimodally expressed transcripts in human umbilical vein endothelial cell (HUVEC) microarray data from 15 individuals. We found that MMP1 mRNA abundance was bimodally distributed in un-treated HUVECs and showed a bimodal response to inflammatory mediator treatment. RT-PCR and MMP1 activity assays confirmed the bimodal regulation and DNA sequencing of 69 individuals identified an MMP1 gene promoter polymorphism that segregated precisely with the MMP1 bimodal expression. Chromatin immunoprecipitation (ChIP) experiments indicated that the transcription factors (TFs) ETS1, ETS2 and GATA3, bind to the MMP1 promoter in the region of this polymorphism and may contribute to the bimodal expression.We describe a simple method to identify putative bimodally expressed RNAs from transcriptome data that is effective yet easy for non-statisticians to understand and use. This method identified bimodal endothelial cell expression of MMP1, which appears to be biologically significant with implications for inflammatory disease. (271 Words).
| S-EPMC3040839 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE23068: Gene expression profiling of HUVEC under basal (resting) conditions GSE23069: Gene expression profiling of HUVEC after stimulation with an inflammatory mediator cocktail Refer to individual Series
2011-07-19 | E-GEOD-23070 | biostudies-arrayexpress
Project description:*MMP1* bimodal expression and differential response to inflammatory mediators is linked to promoter polymorphisms
| PRJNA131673 | ENA
Project description:Recently, we reported on the associations of seven single nucleotide polymorphisms (SNPs) in the promoter region of MMP1 gene with susceptibility to cutaneous melanoma (CM). Considering the reported correlation between MMP1 expression and melanoma progression, we hypothesized that these promoter SNPs might affect CM progression and prognosis. In this study, we examined the associations of seven SNPs with overall survival, as well as six clinicopathological factors in 754 patients with CM. After adjustment for 11 covariates, we observed significant associations of the SNP -422A>T (rs475007) with ulceration status (P=0.012), primary tumor thickness (P=0.040), and anatomic site (P=0.030). We also observed significant associations of the SNP -755T>G (rs498186) with ulceration status (P=0.038) and anatomic site (P=0.003). Two SNPs, -839G>A and -519A>G, were marginally associated with primary tumor thickness, ulceration status, and anatomic site. Furthermore, the frequency of haplotype 2G-G-G-A-A-G-T was higher in patients with ulceration (odds ratio=2.18, 95% confidence interval: 1.08-4.40, P=0.030) compared with those without ulceration. However, we did not find significant associations of these SNPs with overall survival and other clinical factors. As primary tumor thickness and ulceration status are two important indicators of tumor progression and have significant associations with melanoma prognosis, our results suggested that these promoter SNPs in MMP1 might have potential effects on melanoma progression and prognosis by influencing related clinical factors.
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Project description:Differences in gene expression are termed expression level polymorphisms (ELPs). Here, we propose a new ELP class, bimodal ELPs (bELPs), as a criterion to screen for genes that are responsible for natural phenotypic variation and/or that are targeted by balancing selection. bELP genes are characterized by two expression level modes. Genomic scans based on nucleotide sequences are not ideal for identifying genes targeted for selection. A critical concern is that several genes can be present in the selection-targeted regions identified by such scans. This situation indicates the importance of integrating genomic sequence data and other information, such as gene expression data. Comparative transcriptomics is useful for determining evolutionarily and ecologically important polymorphisms. In a genome-wide expression screen of 34 accessions, we identified 344 Arabidopsis thaliana genes exhibiting bELPs. Population genetic analysis revealed that bELP genes had high nucleotide diversities and long linkage disequilibriums. The highest nucleotide diversity (11-fold greater than the genomic mean) was found in the At1g23780 gene, which encodes a putative F-box protein. We observed a clear association between the expression mode and sequence type of the At1g23780 gene. Our results suggest that bELPs will be useful for the screening and functional analysis of genes responsible for phenotypic polymorphisms. Such a "multi-omics" approach has the potential to facilitate the scanning of genes relevant to balanced polymorphisms not only in A. thaliana, but also in other model and non-model organisms.
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Project description:A new genus of specialized pro-resolving mediators (SPM) which include several families of distinct local mediators (lipoxins, resolvins, protectins, and maresins) are actively involved in the clearance and regulation of inflammatory exudates to permit restoration of tissue homeostasis. Classic lipid mediators that are temporally regulated are formed from arachidonic acid, and novel local mediators were uncovered that are biosynthesized from ω-3 poly-unsaturated fatty acids, such as eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid. The biosynthetic pathways for resolvins are constituted by fatty acid lipoxygenases and cyclooxygenase-2 via transcellular interactions established by innate immune effector cells which migrate from the vasculature to inflamed tissue sites. SPM provide local control over the execution of an inflammatory response towards resolution, and include recently recognized actions of SPM such as tissue protection and host defense. The structural families of the SPM do not resemble classic eicosanoids (PG or LT) and are novel structures that function uniquely via pro-resolving cellular and molecular targets. The extravasation of inflammatory cells expressing SPM biosynthetic routes are matched by the temporal provision of essential fatty acids from circulation needed as substrate for the formation of SPM. The present review provides an update and overview of the biosynthetic pathways and actions of SPM, and examines resolution as an integrated component of the inflammatory response and its return to homeostasis via biochemically active resolution mechanisms.
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Project description:The dual oxidase enzymes, DUOX, localized to the respiratory tract epithelium, are important components of innate host defense against bacteria and virus. However, little is known regarding the regulation of DUOX transcription. To better understand DUOX2-mediated mechanisms of antiviral host defense in the airway epithelium, we designed a bidirectional promoter luciferase reporter system to identify important cis-regulatory regions in the human DUOX2/DUOXA2 promoter. In this report, we demonstrate that the genomic region between the translation start sites of DUOX2 and DUOXA2 functions as a bidirectional promoter in human airway tissue. We also identified key regulatory regions on the DUOX2/DUOXA2 promoter that were necessary for both bidirectional and unidirectional transcriptional activity. Importantly, we discovered two functionally important single-nucleotide polymorphisms (SNPs) within the promoter that differentially regulated DUOX2/DUOXA2 transcription in response to exogenous double-stranded DNA. One of these SNPs, rs269855 (enriched in people of African descent), conferred the highest level of DUOX2 promoter activity. The clinical sequelae for individuals who carry this polymorphism remain to be determined.
| S-EPMC3488619 | biostudies-literature
Project description:Exomic studies have demonstrated that innate immune genes exhibit an even higher degree of variation than the majority of other gene families. However, the phenotypic implications of this genetic variation are not well understood, with effects ranging from hypomorphic to silent to hyperfunctioning. In this work, we study the functional consequences of this variation by investigating polymorphisms in gasdermin D, the key pyroptotic effector protein. We find that, although SNPs affecting potential posttranslational modifications did not affect gasdermin D function or pyroptosis, polymorphisms disrupting sites predicted to be structurally important dramatically alter gasdermin D function. The manner in which these polymorphisms alter function varies from conserving normal pyroptotic function to inhibiting caspase cleavage to disrupting oligomerization and pore formation. Further, downstream of inflammasome activation, polymorphisms that cause loss of gasdermin D function convert inflammatory pyroptotic cell death into immunologically silent apoptotic cell death. These findings suggest that human genetic variation can alter mechanisms of cell death in inflammation.
| S-EPMC7062166 | biostudies-literature
Project description:BackgroundAging process is accompanied by a chronic sub-clinical systemic inflammation. This study aimed to assess the association between hearing impairment and polymorphisms of genes encoding cytokines deeply-committed to the inflammatory response and immune homeostasis in an elderly Japanese population. Data were collected in the Longitudinal Study of Aging surveyed biennially between 1997 and 2010. The participants without any missing information at baseline were 1,957 individuals, and the gross accumulated number of 8,675 subjects (40-89 years of age) was analyzed. Two hearing impairment criteria were taken as the better ear pure-tone average (PTABE) greater than 25 dB and greater than 40 dB. We analyzed cumulative data using generalized estimating equations to investigate the effect of 9 polymorphisms, namely, tumor necrosis factor (TNF) α, rs1800630; TNF receptor super family (TNFRSF) 1B, rs1061624; interleukin (IL)-1A, rs1800587; IL-1B, rs16944; IL-4R, rs1801275; IL-6, rs1800796; IL-10, rs1800872; IL-1 receptor-associated kinase 1 (IRAK1), rs1059702; C reactive protein (CRP), rs1130864.ResultsThe odds ratios for the hearing impairment (PTABE >25 dB) risk under additive genetic model were significant in TNF-α rs1800630 and TNFRSF1B rs1061624, which were respectively 1.172 (confidence interval [CI]: 1.005-1.367), 1.211 (CI: 1.053-1.392) in model after adjustment for possible confounders. Using the criterion of PTABE >40 dB as disabling hearing impairment, the association remains significant in TNFRSF1B rs1061624, but not in TNF-α rs1800630. No other polymorphisms showed a significant association.ConclusionsThe present population-based cohort study demonstrated that TNF-α rs1800630 and TNFRSF1B rs1061624 contributed to the incremental risk of hearing impairment in the elderly. TNF-α and TNF receptor interactions play a pivotal role in the pathogenesis of the inflammatory response, and also cause programmed cell death and cell proliferation. The present observation implied the signalling cascades of TNF were involved in ear aging.
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Project description:Tendon inflammation has been implicated in both adaptive connective tissue remodeling and overuse-induced tendinopathy. Lipid mediators control both the initiation and resolution of inflammation, but their roles within tendon are largely unknown. Here, we profiled local shifts in intratendinous lipid mediators via liquid chromatography-tandem mass spectrometry in response to synergist ablation-induced plantaris tendon overuse. Sixty-four individual lipid mediators were detected in homogenates of plantaris tendons from ambulatory control rats. This included many bioactive metabolites of the cyclooxygenase (COX), lipoxygenase (LOX), and epoxygenase (CYP) pathways. Synergist ablation induced a robust inflammatory response at day 3 post-surgery characterized by epitenon infiltration of polymorphonuclear leukocytes and monocytes/macrophages (MΦ), heightened expression of inflammation-related genes, and increased intratendinous concentrations of the pro-inflammatory eicosanoids thromboxane B2 and prostaglandin E2 . By day 7, MΦ became the predominant myeloid cell type in tendon and there were further delayed increases in other COX metabolites including prostaglandins D2 , F2α , and I2 . Specialized pro-resolving mediators including protectin D1, resolvin D2 and D6, as well as related pathway markers of D-resolvins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and lipoxins (15-hydroxy-eicosatetraenoic acid) were also increased locally in response to tendon overuse, as were anti-inflammatory fatty acid epoxides of the CYP pathway (eg, epoxy-eicosatrienoic acids). Nevertheless, intratendinous prostaglandins remained markedly increased even following 28 days of tendon overuse together with a lingering MΦ presence. These data reveal a delayed and prolonged local inflammatory response to tendon overuse characterized by an overwhelming predominance of pro-inflammatory eicosanoids and a relative lack of specialized pro-resolving lipid mediators.
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