Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany.
EMBO Mol Med. 2018 Jan;10(1):107-120. doi: 10.15252/emmm.201707838.
The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non-coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome-wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients ( = 50) with dilated cardiomyopathy (DCM), 80,635 non-protein-coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non-coding RNAs and 1,756 protein-coding transcripts. 65.3% of the SV-eQTLs do not harbor a significant SNV-eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein-coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.
转录组需要通过包括转录因子、增强子和抑制剂以及非编码 RNA 在内的机制进行严格调控。除了这种动态调控之外，真核生物表型变异的很大一部分是通过遗传变异引起的基因转录变化来表达的。在这项研究中，我们评估了全基因组结构基因组变异（SV）及其与人类心脏基因表达的关联。我们检测到了 3898 个个体 SV，这些 SV 影响所有类别的基因转录物（例如 mRNA、miRNA、lncRNA）和调节基因组区域（例如增强子或 TFBS）。在一组患有扩张型心肌病（DCM）的患者（n=50）中，SV 导致基因组的 80635 个非蛋白编码元件缺失或重复，其中包含 3758 个长非编码 RNA 和 1756 个蛋白编码转录物。65.3%的 SV-eQTL 不包含显著的 SNV-eQTL，对于具有这两类关联的区域，我们发现了类似的效应大小。对于缺失的蛋白编码外显子，我们发现相关转录物的下调，而重复事件在所有事件中均未显示出显著变化。总之，我们首先描述了与 DCM 引起的心衰相关的 SV 相关的基因组变异性，并剖析了它们对转录组的影响。总体而言，SV 可解释高达 7.5%的心脏基因表达变异，这突显了在个体基因组背景下研究人类心肌基因表达的重要性。这对心脏适应不良的基础机制、生物标志物和（基因）治疗研究的研究具有直接意义。
