Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4.
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.
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Chuan
C
Wang
Johanna K
JK
Sandling
Niklas
N
Hagberg
Olof
O
Berggren
Snaevar
S
Sigurdsson
Olof
O
Karlberg
Lars
L
Rönnblom
Maija-Leena
ML
Eloranta
Ann-Christine
AC
Syvänen
D047369:Chromatin Immunoprecipitation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor / Q000235:genetics*
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human