Pahl Matthew C, Erdman Robert, Kuivaniemi Helena, Lillvis John H, Elmore James R, Tromp Gerard
Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA.
Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Int J Mol Sci. 2015 May 18;16(5):11229-58. doi: 10.3390/ijms160511229.
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.
我们研究了人类腹主动脉瘤（AAA）中基因表达的转录调控。与非动脉瘤对照相比，我们先前在人类AAA组织中鉴定出3274个差异表达基因。选择了四种表达的转录因子（ELF1、ETS2、STAT5和RUNX1）进行全基因组染色质免疫沉淀。转录因子结合在4760个不同基因中富集（错误发现率<0.05），其中713个在AAA中差异表达。使用基因本体论（GO）、KEGG和网络分析进行的功能分类显示，在包括“白细胞迁移”（错误发现率=3.09×10 - 05）和“细胞内蛋白激酶级联反应”（错误发现率=6.48×10 - 05）在内的几个生物学过程中存在富集。在对照主动脉中，最显著的GO类别与AAA样本中的不同，包括“细胞骨架组织”（错误发现率=1.24×10 - 06）和“小GTP酶介导的信号转导”（错误发现率=1.24×10 - 06）。在AAA组织中上调的基因在GO类别“白细胞迁移”（错误发现率=1.62×10 - 11）、“免疫反应激活”（错误发现率=8.44×10 - 11）、“T细胞激活”（错误发现率=4.14×10 - 10）和“淋巴细胞激活调节”（错误发现率=2.45×10 - 09）中显示出高度显著的富集，而下调基因在GO类别“细胞骨架组织”（错误发现率=7.84×10 - 05）、“肌肉细胞发育”（错误发现率=1.00×10 - 04）和“器官形态发生”（错误发现率=3.00×10 - 04）中富集。定量PCR分析证实了转录因子结合位点的一个子集，包括MTMR11、DUSP10、ITGAM、MARCH1、HDAC8、MMP14、MAGI1、THBD和SPOCK1中的那些位点。
