BACKGROUND Genome-wide association studies have identified over 160 loci that are associated with coronary artery disease. As with other complex human diseases, risk in coronary disease loci is determined primarily by altered expression of the causal gene, due to variation in binding of transcription factors and chromatin-modifying proteins that directly regulate the transcriptional apparatus. We have previously identified a coronary disease network downstream of the disease-associated transcription factor TCF21, and in work reported here extends these studies to investigate the mechanisms by which it interacts with the AP-1 transcription complex to regulate local epigenetic effects in these downstream coronary disease loci. METHODS Genomic studies, including chromatin immunoprecipitation sequencing, RNA sequencing, and protein-protein interaction studies, were performed in human coronary artery smooth muscle cells. RESULTS We show here that TCF21 and JUN regulate expression of two presumptive causal coronary disease genes, SMAD3 and CDKN2B-AS1, in part by interactions with histone deacetylases and acetyltransferases. Genome-wide TCF21 and JUN binding is jointly localized and particularly enriched in coronary disease loci where they broadly modulate H3K27Ac and chromatin state changes linked to disease-related processes in vascular cells. Heterozygosity at coronary disease causal variation, or genome editing of these variants, is associated with decreased binding of both JUN and TCF21 and loss of expression in cis, supporting a transcriptional mechanism for disease risk. CONCLUSIONS These data show that the known chromatin remodeling and pioneer functions of AP-1 are a pervasive aspect of epigenetic control of transcription, and thus, the risk in coronary disease-associated loci, and that interaction of AP-1 with TCF21 to control epigenetic features, contributes to the genetic risk in loci where they co-localize.

中文翻译：

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TCF21 和 AP-1 通过表观遗传修饰相互作用以调节冠状动脉疾病基因的表达。

背景全基因组关联研究已经确定了超过 160 个与冠状动脉疾病相关的位点。与其他复杂的人类疾病一样，冠状动脉疾病基因座的风险主要由致病基因的表达改变决定，这是由于转录因子和直接调节转录装置的染色质修饰蛋白结合的变化。我们之前已经确定了疾病相关转录因子 TCF21 下游的冠状动脉疾病网络，并且在此报告的工作中扩展了这些研究以研究它与 AP-1 转录复合物相互作用以调节这些下游冠状动脉中的局部表观遗传效应的机制疾病位点。方法 基因组研究，包括染色质免疫沉淀测序、RNA 测序、和蛋白质-蛋白质相互作用研究，在人冠状动脉平滑肌细胞中进行。结果 我们在此显示，TCF21 和 JUN 调节两种假定的冠状动脉疾病致病基因 SMAD3 和 CDKN2B-AS1 的表达，部分是通过与组蛋白脱乙酰酶和乙酰转移酶的相互作用。全基因组 TCF21 和 JUN 结合共同定位并特别富集在冠状动脉疾病位点，它们广泛调节与血管细胞中疾病相关过程相关的 H3K27Ac 和染色质状态变化。冠心病因果变异的杂合性，或这些变异的基因组编辑，与 JUN 和 TCF21 的结合减少以及顺式表达的丧失有关，支持疾病风险的转录机制。