Medical Genomics, UCL Cancer Institute, University College London, London, UK ; Current address: Translational Cancer Therapeutics, CR-UK London Research Institute, Lincoln's Inn Fields, London, UK.
Medical Genomics, UCL Cancer Institute, University College London, London, UK.
Genome Med. 2014 Mar 5;6(3):19. doi: 10.1186/gm536. eCollection 2014.
Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment's influence on the epigenome, and therefore genome function, as well as conversely the genome's facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.
In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.
We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.
This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
常见的人类疾病是由遗传易感性以及环境因素的复杂相互作用引起的。由于环境对表观基因组的影响，以及基因组对表观基因组功能的促进作用，分析这种调节水平可能会增加我们对疾病发病机制的认识。
为了确定人类特有的表观遗传影响，我们进行了一项新的全基因组 DNA 甲基化分析，比较了人类、黑猩猩和恒河猴。
我们已经确定，与其他灵长类动物相比，免疫性白三烯 B4 受体（LTB4R，BLT1 受体）是外周血中最具表观遗传差异的人类基因。这种差异是由于启动子中人类特异性去甲基化的协调活跃状态和人类特异性增加的基因体甲基化所致。该基因在先天免疫中具有重要意义，LTB4/LTB4R 途径参与了一系列人类炎症性疾病的发病机制。这一发现通过额外的中性粒细胞特异性 DNA 甲基组和淋巴母细胞样 H3K4me3 染色质比较数据得到了证实。此外，我们通过功能分析表明，该受体在人类外周血单核细胞中表达增加，对 LTB4 配体的反应高于恒河猴。全基因组范围内，我们还发现人类种特异性差异甲基化区域（human s-DMRs）在 CpG 岛岸比在岛内更为普遍，并且在后一种情况下与 CTCF 基序相关。
这一结果进一步强调了人类免疫系统的独特性质，即使与非常密切相关的灵长类动物相比，它的适应性也存在差异，以及比较表观基因组学在识别和理解人类独特性方面的强大功能。
