Abstract
We investigated transcriptional control of gene expression in human abdominal aortic aneurysm (AAA). We previously identified 3274 differentially expressed genes in human AAA tissue compared to non-aneurysmal controls. Four expressed transcription factors (ELF1, ETS2, STAT5 and RUNX1) were selected for genome-wide chromatin immunoprecipitation. Transcription factor binding was enriched in 4760 distinct genes (FDR < 0.05), of which 713 were differentially expressed in AAA. Functional classification using Gene Ontology (GO), KEGG, and Network Analysis revealed enrichment in several biological processes including “leukocyte migration” (FDR = 3.09 × 10−05) and “intracellular protein kinase cascade” (FDR = 6.48 × 10−05). In the control aorta, the most significant GO categories differed from those in the AAA samples and included “cytoskeleton organization” (FDR = 1.24 × 10−06) and “small GTPase mediated signal transduction” (FDR = 1.24 × 10−06). Genes up-regulated in AAA tissue showed a highly significant enrichment for GO categories “leukocyte migration” (FDR = 1.62 × 10−11), “activation of immune response” (FDR = 8.44 × 10−11), “T cell activation” (FDR = 4.14 × 10−10) and “regulation of lymphocyte activation” (FDR = 2.45 × 10−09), whereas the down-regulated genes were enriched in GO categories “cytoskeleton organization” (FDR = 7.84 × 10−05), “muscle cell development” (FDR = 1.00 × 10−04), and “organ morphogenesis” (FDR = 3.00 × 10−04). Quantitative PCR assays confirmed a sub-set of the transcription factor binding sites including those in MTMR11, DUSP10, ITGAM, MARCH1, HDAC8, MMP14, MAGI1, THBD and SPOCK1.
Highlights
Abdominal aortic aneurysms (AAAs) are a chronic disease whose pathogenesis is poorly understood [1,2,3,4,5,6]
The fourth transcription factors (TFs) studied here, STAT5 was found to play a significant role in the transcriptional regulation of many members of the complement cascade [14]. It is stimulated in the JAK-STAT pathway, where a trans-membrane binding protein will bind to a cytokine which results in a conformational change of the receptor’s intercellular region that induces the phosphorylation of the STAT protein by Janus kinase (JAK), which can lead to the formation of a dimer (STAT5A/B) or a tetramer (STAT5A)
We tested antibody specificity to ensure that we can identify binding sites specific for ELF1, ETS2, and RUNX1, the TFs chosen for the study based on our previous in silico analyses [8], as well as STAT5 identified as a key regular in our previous study on the complement cascade [14]
Summary
Abdominal aortic aneurysms (AAAs) are a chronic disease whose pathogenesis is poorly understood [1,2,3,4,5,6]. The binding behavior of ELF1 and ETS2 differs in that ELF1 binds strictly to its core motif, while ETS2 binds weakly to its targets [13] Both ELF1 and ETS2 are expressed in human AAA and non-aneurysmal infrarenal aorta with ELF1 showing significantly increased expression in AAA (Table 1). The fourth TF studied here, STAT5 (signal transducer and activator of transcription 5) was found to play a significant role in the transcriptional regulation of many members of the complement cascade [14] It is stimulated in the JAK-STAT pathway, where a trans-membrane binding protein will bind to a cytokine (interleukins, erythropoietin, thrombopoietin, growth hormone, and prolactin [20]) which results in a conformational change of the receptor’s intercellular region that induces the phosphorylation of the STAT protein by Janus kinase (JAK), which can lead to the formation of a dimer (STAT5A/B) or a tetramer (STAT5A). Combined analysis with ChIP-chip and genome-wide mRNA expression data on human AAA tissue was carried out to provide biologically relevant and disease-centered information
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