IRF3, IRF5 and IRF9 are transcription factors, which play distinct roles in the regulation of antiviral and inflammatory responses. The determinants that mediate IRF-specific enhancer selection are not fully understood. To uncover regions occupied predominantly by IRF3, IRF5 or IRF9, we performed ChIP-seq experiments in activated murine dendritic cells. The identified regions were analysed with respect to the enrichment of DNA motifs, the interferon-stimulated response element (ISRE) and ISRE half-site variants, and chromatin accessibility. Using a machine learning method, we investigated the predictability of IRF-dominance. We found that IRF5-dominant regions differed fundamentally from the IRF3- and IRF9-dominant regions: ISREs were rare, while the NFKB motif and special ISRE half-sites, such as 5′-GAGA-3′ and 5′-GACA-3′, were enriched. IRF3- and IRF9-dominant regions were characterized by the enriched ISRE motif and lower frequency of accessible chromatin. Enrichment analysis and the machine learning method uncovered the features that favour IRF3 or IRF9 dominancy (e.g. a tripartite form of ISRE and motifs for NF-κB for IRF3, and the GAS motif and certain ISRE variants for IRF9). This study contributes to our understanding of how IRF members, which bind overlapping sets of DNA sequences, can initiate signal-dependent responses without activating superfluous or harmful programmes.
Objectives Impaired vascular pathophysiology and increased cardiovascular (CV) mortality are associated with rheumatoid arthritis (RA). To date, no genomic analysis of RA- and RA treatment-related vascular pathophysiology has been published. In this pilot study, we performed gene expression profiling in association with vascular pathophysiology in RA patients. Methods Sixteen and 19 biologic-naïve RA patients were included in study 1 and study 2, respectively. In study 1, genetic signatures determined by microarray were related to flow-mediated vasodilation (FMD), pulse-wave velocity (PWV), and common carotid intima-media thickness (IMT) of patients. In study 2, clinical response (cR) vs non-response (cNR) to 1-year etanercept (ETN) or certolizumab pegol (CZP) treatment, as well as “vascular” response (vR) vs non-response (vNR) to biologics, were also associated with genomic profiles. Multiple testing could not be performed due to the relatively small number of patients; therefore, our pilot study may lack power. Results In study 1, multiple genes were up- or downregulated in patients with abnormal vs normal FMD, IMT, and PWV. In study 2, there were 13 cR and 6 cNR anti-tumor necrosis factor (TNF)-treated patients. In addition, 10, 9, and 8 patients were FMD-20%, IMT-20%, and PWV-20% responders. Again, vascular responder status was associated with changes of the expression of various genes. The highest number of genes showing significant enrichment were involved in positive regulation of immune effector process, regulation of glucose transport, and Golgi vesicle budding. Conclusion Differential expression of multiple genetic profiles may be associated with vascular pathophysiology associated with RA. Moreover, distinct genetic signatures may also be associated with clinical and vascular responses to 1-year anti-TNF treatment. Electronic supplementary material The online version of this article (10.1186/s13075-019-1862-6) contains supplementary material, which is available to authorized users.
BackgroundAccelerated atherosclerosis and cardiovascular (CV) disease have been associated with rheumatoid arthritis (RA). Many genes have been implicated in atherosclerosis, RA or both. However, most of these studies described SNPs in CD40, SMAD3, HLADR, CTLA4 and other alleles. Very few studies on genetic signatures have been performed that would link RA and CV pathology. We have previously associated some genomic profiles with pathological carotid atherosclerosis (ccIMT), arterial stiffness (PWV) and brachial artery flow-mediated vasodilation (FMD). In other studies we have also found 165 genes that separated anti-TNF responder patients from non-responders.ObjectivesHere we looked for associations between clinical and “vascular” response to biologics and vascular pathology in RA patients.MethodsIn this study, 19 RA patients were treated with either etanercept (ETN) or certolizumab pegol (CZP) for one year. We separated responders (R) and non-responders (NR) according to EULAR response criteria. Microarray gene expression study was performed (Affymetrix) followed by analysis using the GeneSpring software, hierarchy clustering and principal component analysis (PCA). “Vascular response” (VR) to biologics was defined as an at least 20% improvement in FMD, ccIMT or PWV. Good Vascular Response (GVR) was defined as an at least 20% improvement in two or three of these variables.ResultsAmong the 19 patients, 13 were R and 6 were NR. With respect to VR, FMD, ccIMT and PWV responded to anti-TNF treatment in 10, 9 and 8 patients, respectively. GVR was observed in 8 patients and 5 patients had VR in all 3 parameters. When comparing clinical response and VR, 7 out of 8 patients showing GVR also had good clinical response to biologics. Up-regulation of 99 and down-regulation of 67 genes separated clinical R and NR patients. Significant correlation was found between ccIMT improvement upon biological therapy and clinical response (R=0.418, p=0.04).ConclusionsGenomic signature analysis may be able to separate clinical responders and non-responders to biologics, as well as patients that show or do not show imporvement of vascular pathology.Disclosure of InterestNone declared
BackgroundAccelerated atherosclerosis, increased cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA). In single SNP studies, CD40, HLADRB1, MTHFR, SMAD3 and possibly other alleles have been associated with cardiovascular disease (CVD) or vascular pathophysiology in RA. Endothelial dysfunction, carotid atherosclerosis and arterial stiffness that may predict the development of CVD are assessed by bracial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV), respectively.ObjectivesIn this study, we wished to determine expression profiles of multiple genes that may differentiate between physiological and pathological vascular function in RA.MethodsAltogether 16 RA patients were recruited. FMD, ccIMT and PWV were assessed in all patients using standard B-mode ultrasound techniques. FMD <6%, ccIMT >0.6mm and PWV >9 m/sec were considered abnormal. Peripheral blood mononuclear cell samples were obtained and used in microarray. The signature of those genes were determined by principal component analysis (PCA) and hierarchic clustering (GeneSpring software), which significantly differentiated patient subsets with normal vs abnormal FMD, ccIMT and PWV.ResultsAmong RA patients, 11 had low (impaired) and 5 had normal FMD, 11 had high (increased) and 5 had normal ccIMT and 9 had high (increased) and 7 had normal PWV. Altogether 20 genes differentiated patients with low vs normal FMD. Altogether 33 genes separated high vs normal PWV. Finally, 240 genes differentiated increased vs normal ccIMT.ConclusionsUsing microarray, genetic signatures may differentiate RA patients with and without vascular pathology.Disclosure of InterestNone declared
The antiviral state, an initial line of defense against viral infection, is established by a set of IFN-stimulated genes (ISGs) encoding antiviral effector proteins. The effector ISGs are transcriptionally regulated by type I IFNs mainly via activation of IFN-stimulated gene factor 3 (ISGF3). In this study, the regulatory elements of effector ISGs were characterized to determine the (epi)genetic features that enable their robust induction by type I IFNs in multiple cell types. We determined the location of regulatory elements, the DNA motifs, the occupancy of ISGF3 subunits (IRF9, STAT1, and STAT2) and other transcription factors, and the chromatin accessibility of 37 effector ISGs in murine dendritic cells. The IFN-stimulated response element (ISRE) and its tripartite version occurred most frequently in the regulatory elements of effector ISGs than in any other tested ISG subsets. Chromatin accessibility at their promoter regions was similar to most other ISGs but higher than at the promoters of inflammation-related cytokines, which were used as a reference gene set. Most effector ISGs (81.1%) had at least one ISGF3 binding region proximal to the transcription start site (TSS), and only a subset of effector ISGs (24.3%) was associated with three or more ISGF3 binding regions. The IRF9 signals were typically higher, and ISRE motifs were “stronger” (more similar to the canonical sequence) in TSS-proximal versus TSS-distal regulatory regions. Moreover, most TSS-proximal regulatory regions were accessible before stimulation in multiple cell types. Our results indicate that “strong” ISRE motifs and universally accessible promoter regions that permit robust, widespread induction are characteristic features of effector ISGs.
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