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.
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.
Authors: Siddhartha P Kar; Jonathan P Tyrer; Qiyuan Li; Kate Lawrenson; Katja K H Aben; Hoda Anton-Culver; Natalia Antonenkova; Georgia Chenevix-Trench; Helen Baker; Elisa V Bandera; Yukie T Bean; Matthias W Beckmann; Andrew Berchuck; Maria Bisogna; Line Bjørge; Natalia Bogdanova; Louise Brinton; Angela Brooks-Wilson; Ralf Butzow; Ian Campbell; Karen Carty; Jenny Chang-Claude; Yian Ann Chen; Zhihua Chen; Linda S Cook; Daniel Cramer; Julie M Cunningham; Cezary Cybulski; Agnieszka Dansonka-Mieszkowska; Joe Dennis; Ed Dicks; Jennifer A Doherty; Thilo Dörk; Andreas du Bois; Matthias Dürst; Diana Eccles; Douglas F Easton; Robert P Edwards; Arif B Ekici; Peter A Fasching; Brooke L Fridley; Yu-Tang Gao; Aleksandra Gentry-Maharaj; Graham G Giles; Rosalind Glasspool; Ellen L Goode; Marc T Goodman; Jacek Grownwald; Patricia Harrington; Philipp Harter; Alexander Hein; Florian Heitz; Michelle A T Hildebrandt; Peter Hillemanns; Estrid Hogdall; Claus K Hogdall; Satoyo Hosono; Edwin S Iversen; Anna Jakubowska; James Paul; Allan Jensen; Bu-Tian Ji; Beth Y Karlan; Susanne K Kjaer; Linda E Kelemen; Melissa Kellar; Joseph Kelley; Lambertus A Kiemeney; Camilla Krakstad; Jolanta Kupryjanczyk; Diether Lambrechts; Sandrina Lambrechts; Nhu D Le; Alice W Lee; Shashi Lele; Arto Leminen; Jenny Lester; Douglas A Levine; Dong Liang; Jolanta Lissowska; Karen Lu; Jan Lubinski; Lene Lundvall; Leon Massuger; Keitaro Matsuo; Valerie McGuire; John R McLaughlin; Iain A McNeish; Usha Menon; Francesmary Modugno; Kirsten B Moysich; Steven A Narod; Lotte Nedergaard; Roberta B Ness; Heli Nevanlinna; Kunle Odunsi; Sara H Olson; Irene Orlow; Sandra Orsulic; Rachel Palmieri Weber; Celeste Leigh Pearce; Tanja Pejovic; Liisa M Pelttari; Jennifer Permuth-Wey; Catherine M Phelan; Malcolm C Pike; Elizabeth M Poole; Susan J Ramus; Harvey A Risch; Barry Rosen; Mary Anne Rossing; Joseph H Rothstein; Anja Rudolph; Ingo B Runnebaum; Iwona K Rzepecka; Helga B Salvesen; Joellen M Schildkraut; Ira Schwaab; Xiao-Ou Shu; Yurii B Shvetsov; Nadeem Siddiqui; Weiva Sieh; Honglin Song; Melissa C Southey; Lara E Sucheston-Campbell; Ingvild L Tangen; Soo-Hwang Teo; Kathryn L Terry; Pamela J Thompson; Agnieszka Timorek; Ya-Yu Tsai; Shelley S Tworoger; Anne M van Altena; Els Van Nieuwenhuysen; Ignace Vergote; Robert A Vierkant; Shan Wang-Gohrke; Christine Walsh; Nicolas Wentzensen; Alice S Whittemore; Kristine G Wicklund; Lynne R Wilkens; Yin-Ling Woo; Xifeng Wu; Anna Wu; Hannah Yang; Wei Zheng; Argyrios Ziogas; Thomas A Sellers; Alvaro N A Monteiro; Matthew L Freedman; Simon A Gayther; Paul D P Pharoah Journal: Cancer Epidemiol Biomarkers Prev Date: 2015-07-24 Impact factor: 4.254
Authors: David G Saliba; Andreas Heger; Hayley L Eames; Spyros Oikonomopoulos; Ana Teixeira; Katrina Blazek; Ariadne Androulidaki; Daniel Wong; Fui G Goh; Miriam Weiss; Adam Byrne; Manolis Pasparakis; Jiannis Ragoussis; Irina A Udalova Journal: Cell Rep Date: 2014-08-21 Impact factor: 9.423
Authors: Adam E Handel; Geir K Sandve; Giulio Disanto; Lahiru Handunnetthi; Gavin Giovannoni; Sreeram V Ramagopalan Journal: BMC Med Genomics Date: 2013-10-30 Impact factor: 3.063