Division of Cardiovascular Medicine and Cardiovascular Institute, School of Medicine, Stanford University, 300 Pasteur Dr., Falk CVRC, Stanford, CA, 94305, USA.
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA.
Genome Med. 2019 May 2;11(1):23. doi: 10.1186/s13073-019-0635-9.
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.
Genomic studies, including chromatin immunoprecipitation sequencing, RNA sequencing, and protein-protein interaction studies, were performed in human coronary artery smooth muscle cells.
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.
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.
全基因组关联研究已经确定了 160 多个与冠状动脉疾病相关的基因座。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是由于转录因子结合的改变和直接调节转录装置的染色质修饰蛋白的改变导致的致病基因表达的改变。我们之前已经确定了与疾病相关转录因子 TCF21 下游的冠状动脉疾病网络，并且在本报告中扩展了这些研究，以研究其与 AP-1 转录复合物相互作用的机制，以调节这些下游冠状动脉疾病基因座中的局部表观遗传效应。
在人冠状动脉平滑肌细胞中进行了基因组研究，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。
我们在这里表明，TCF21 和 JUN 通过与组蛋白去乙酰化酶和乙酰转移酶的相互作用，部分调节两个假定的因果冠状动脉疾病基因 SMAD3 和 CDKN2B-AS1 的表达。全基因组 TCF21 和 JUN 结合共同定位，并且特别富集在冠状动脉疾病基因座中，它们广泛调节 H3K27Ac 和与血管细胞中疾病相关过程相关的染色质状态变化。冠状动脉疾病因果变异的杂合性或这些变体的基因组编辑与 JUN 和 TCF21 的结合减少以及顺式表达丧失有关，支持疾病风险的转录机制。
这些数据表明，AP-1 的已知染色质重塑和先驱功能是转录表观遗传控制的普遍方面，因此，与冠状动脉疾病相关基因座的风险，以及 AP-1 与 TCF21 相互作用以控制表观遗传特征，有助于它们共同定位的基因座中的遗传风险。
