Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
Chemosphere. 2018 Dec;212:915-926. doi: 10.1016/j.chemosphere.2018.09.010. Epub 2018 Sep 3.
PM exposure is strongly linked to cardiac disease. Subtle epigenetic or transcriptional alterations induced by PM might contribute to pathogenesis and disease susceptibility of cardiac disease. It is still a major challenge to identify biological targets in human genetics. Human cardiomyocytes AC16 was chosen as cell model. Epigenetic effect of PM in AC16 was analyzed using Illumina HumanMethylation 450 K BeadChip. Meanwhile the transcriptomic profiling was performed by Affymetrix microarray. PM induced genome wide variation of DNA methylation pattern, including differentially methylated CpGs in promoter region. Then gene ontology analysis demonstrated differentially methylated genes were significantly clustered in pathways in regulation of apoptotic process, cell death and metabolic pathways, or associated with ion binding and shuttling. Correlation of the methylome and transcriptome revealed a clear bias toward transcriptional suppression by hypermethylation or activation by hypomethylation. Identified 386 genes which exhibited both differential methylation and expression were functionally associated with pathways including cardiovascular system development, regulation of blood vessel size, vasculature development, p53 pathway, AC-modulating/inhibiting GPCRs pathway and cellular response to metal ion/inorganic substance. Disease ontology demonstrated their prominent role in cardiac diseases and identified 14 cardiac-specific genes (ANK2, AQP1 et al.). PPI network analysis revealed 6 novel genes (POLR2I, LEP, BRIX1, ADCY6, INSL3, RARS). Those genes were then verified by qRT-PCR. Thus, in AC16, PM alters the methylome and transcriptome of genes might be relevant for PM-/heart-associated diseases. Result gives additional insight in PM relative cardiac diseases/associated genes and the potential mechanisms that contribute to PM related cardiac disease.
PM 暴露与心脏病强烈相关。PM 诱导的微妙表观遗传或转录改变可能有助于心脏病的发病机制和疾病易感性。在人类遗传学中识别生物靶标仍然是一个主要挑战。选择人类心肌细胞 AC16 作为细胞模型。使用 Illumina HumanMethylation 450K BeadChip 分析 PM 在 AC16 中的表观遗传效应。同时，通过 Affymetrix 微阵列进行转录组谱分析。PM 诱导了全基因组 DNA 甲基化模式的变化，包括启动子区域的差异甲基化 CpG。然后，基因本体分析表明，差异甲基化基因显著聚类在凋亡过程、细胞死亡和代谢途径的调节途径中，或与离子结合和转运有关。甲基组和转录组的相关性表明，超甲基化倾向于转录抑制，而低甲基化倾向于转录激活。确定了 386 个表现出差异甲基化和表达的基因，它们与包括心血管系统发育、血管大小调节、血管发育、p53 途径、AC 调节/抑制 GPCRs 途径和细胞对金属离子/无机物质的反应等途径有关。疾病本体论表明它们在心脏病中起着重要作用，并确定了 14 个心脏特异性基因（ANK2、AQP1 等）。PPI 网络分析揭示了 6 个新基因（POLR2I、LEP、BRIX1、ADCY6、INSL3、RARS）。然后通过 qRT-PCR 验证这些基因。因此，在 AC16 中，PM 改变与 PM/心脏相关疾病相关的基因的甲基组和转录组可能是相关的。该结果为 PM 相对心脏病/相关基因提供了额外的见解，并为 PM 相关心脏病的潜在机制提供了依据。
