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Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. (Systemic Autoimmune Diseases)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. (Systemic Autoimmune Diseases)
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2013 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no 1, 96-103 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The transcription factors interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE).

OBJECTIVE:

To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs).

METHODS:

Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants.

RESULTS:

More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants.

CONCLUSIONS:

By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE.

Place, publisher, year, edition, pages
2013. Vol. 72, no 1, 96-103 p.
Keyword [en]
interferon regulatory factor 5, signal transducer and activator of transcription 4, systemic lupus erythematosus, ChIP-seq
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-179118DOI: 10.1136/annrheumdis-2012-201364ISI: 000312407800016PubMedID: 22730365OAI: oai:DiVA.org:uu-179118DiVA: diva2:543452
Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
In thesis
1. DNA Sequence Variants in Human Autoimmune Diseases
Open this publication in new window or tab >>DNA Sequence Variants in Human Autoimmune Diseases
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human autoimmune diseases are hallmarked by inappropriate loss-of-tolerance and self-attacking response of the immune system. Studies included in this thesis are focusing on the implication and functional impact of genetic factors in three autoimmune diseases rheumatoid arthritis (RA), asthma, and systemic lupus erythematosus (SLE).

Using genetic association studies, we found in study I and II that sequence variants of the interferon regulatory factor 5 (IRF5) gene were associated with RA and asthma, and the associations were more pronounced in certain disease subtypes. Distinct association patterns or risk alleles of the IRF5 gene variants were revealed in different diseases, indicating that IRF5 contributes to disease manifestations in a dose-dependent manner. In study III, we found that seven out of eight genetic risk loci for SLE, which were originally identified in East Asian populations, also conferred disease risk with the same risk alleles and comparable magnitudes of effect sizes in Caucasians. Remarkable differences in risk allele frequencies were observed for all associated loci across ethnicities, which seems to be the major source of genetic heterogeneity for SLE. In study IV we explored an exhaustive spectrum of sequence variants in the genes inhibitor of kappa light polypeptide gene enhancer in B-cells kinase epsilon (IKBKE) and interferon induced with helicase C domain 1 (IFIH1) by gene resequencing, and identified nine variants in IKBKE and three variants in IFIH1 as genetic risk factors for SLE. One of the associated variants may influence splicing of IKBKE mRNA. In study V we provided genome-wide transcriptional regulatory profiles for IRF5 and signal transducer and activator of transcription 4 (STAT4) using chromatin immunoprecipitation-sequencing (ChIP-seq). The target genes of IRF5 and STAT4 were found to play active roles in pathways related with inflammatory response, and their expression patterns were characteristic for SLE patients. We also identified potential cooperative transcription factors for IRF5 and STAT4, and disease-associated sequence variants which may affect the regulatory function of IRF5 and STAT4.

In conclusion, this thesis illuminates the contribution of several genetic risk factors to susceptibility of human autoimmune diseases, which facilitates our understanding of the genetic basis of their pathogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 808
Keyword
Association study, Gene resequencing, ChIP-seq, Type I interferon system, Systemic lupus erythematosus, Rheumatoid arthritis, Asthma
National Category
Medical and Health Sciences
Research subject
Medical Genetics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-179189 (URN)978-91-554-8459-0 (ISBN)
Public defence
2012-10-18, Enghoffsalen, University Hospital, Entrance 50, Ground Floor, Uppsala, 09:15 (English)
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Supervisors
Available from: 2012-09-27 Created: 2012-08-09 Last updated: 2013-01-23Bibliographically approved

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Wang, ChuanSandling, Johanna KHagberg, NiklasBerggren, OlofKarlberg, OlofRönnblom, LarsEloranta, Maija-LeenaSyvänen, Ann-Christine

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