Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg.
Biozentrum, University of Basel and Swiss Institute of Bioinformatics, 4056 Basel, Switzerland.
Nucleic Acids Res. 2015 Oct 15;43(18):8839-55. doi: 10.1093/nar/gkv863. Epub 2015 Sep 3.
We previously showed that disease-linked metabolic genes are often under combinatorial regulation. Using the genome-wide ChIP-Seq binding profiles for 93 transcription factors in nine different cell lines, we show that genes under high regulatory load are significantly enriched for disease-association across cell types. We find that transcription factor load correlates with the enhancer load of the genes and thereby allows the identification of genes under high regulatory load by epigenomic mapping of active enhancers. Identification of the high enhancer load genes across 139 samples from 96 different cell and tissue types reveals a consistent enrichment for disease-associated genes in a cell type-selective manner. The underlying genes are not limited to super-enhancer genes and show several types of disease-association evidence beyond genetic variation (such as biomarkers). Interestingly, the high regulatory load genes are involved in more KEGG pathways than expected by chance, exhibit increased betweenness centrality in the interaction network of liver disease genes, and carry longer 3' UTRs with more microRNA (miRNA) binding sites than genes on average, suggesting a role as hubs integrating signals within regulatory networks. In summary, epigenetic mapping of active enhancers presents a promising and unbiased approach for identification of novel disease genes in a cell type-selective manner.
我们之前曾表明，与疾病相关的代谢基因通常受到组合调控。利用 93 种转录因子在 9 种不同细胞系中的全基因组 ChIP-Seq 结合谱，我们发现高调控负荷基因在细胞类型之间显著富集与疾病相关。我们发现转录因子负荷与基因的增强子负荷相关，因此可以通过对活性增强子进行表观基因组映射来鉴定高调控负荷基因。在来自 96 种不同细胞和组织类型的 139 个样本中鉴定出高增强子负荷基因，以细胞类型选择性的方式一致富集与疾病相关的基因。潜在基因不仅限于超级增强子基因，并且除遗传变异（如生物标志物）之外，还显示出几种类型的疾病关联证据。有趣的是，高调控负荷基因比预期更参与更多的 KEGG 途径，在肝病基因相互作用网络中具有更高的介数中心性，并且携带比平均基因更长的 3'UTR ，具有更多的 microRNA（miRNA）结合位点，表明其作为整合调控网络内信号的枢纽的作用。总之，活性增强子的表观基因组图谱为以细胞类型选择性的方式鉴定新的疾病基因提供了一种有前途且无偏的方法。
