Hui-Yuen Joyce S, Zhu Lisha, Wong Lai Ping, Jiang Kaiyu, Chen Yanmin, Liu Tao, Jarvis James N
Division of Pediatric Rheumatology, Steven and Alexandra Cohen Children's Medical Center, 1991 Marcus Avenue, Suite M100, Lake Success, NY, 11042, USA.
Department of Pediatrics, Hofstra-Northwell School of Medicine, Hempstead, NY, 11549, USA.
Arthritis Res Ther. 2016 Dec 1;18(1):281. doi: 10.1186/s13075-016-1169-9.
Systemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability. Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within noncoding regions of the human genome. We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.
We used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We also interrogated available data in Roadmap Epigenomics for CD4 T cells and CD19 B cells to identify these same elements in lymphoid cells.
All three cell types demonstrated enrichment of enhancer-associated histone marks compared with genomic background within LD blocks encoded by SLE-associated SNPs. In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background. In CD19 B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.
Much of the genetic risk for SLE lies within or near genomic regions of disease-relevant cells that are enriched for epigenetic marks associated with enhancer function. Elucidating the specific roles of these noncoding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.
系统性红斑狼疮（SLE）是一种多系统复杂疾病，环境与遗传基因相互作用，产生个体间存在差异的广泛表型。在近期全基因组关联研究中显示的46个单核苷酸多态性（SNP）中，有30个位于人类基因组的非编码区域。因此，我们试图识别并描述位于这些感兴趣区域内的功能元件（除基因外）。
我们采用染色质免疫沉淀测序法，以识别与成年中性粒细胞中增强子功能相关的表观遗传标记，从而确定增强子相关组蛋白标记是否在包含46个感兴趣SNP的连锁不平衡（LD）区域内富集。我们还查询了表观基因组路线图中CD4 T细胞和CD19 B细胞的现有数据，以在淋巴细胞中识别这些相同的元件。
与SLE相关SNP编码的LD区域内的基因组背景相比，所有三种细胞类型均显示增强子相关组蛋白标记富集。此外，在这些LD区域的启动子区域内，所有三种细胞类型均显示转录因子结合位点在基因组背景之上富集。在CD19 B细胞中，除一个感兴趣的LD区域外，其他所有区域也显示增强子相关组蛋白标记富集。
SLE的许多遗传风险位于疾病相关细胞的基因组区域内或附近，这些区域富含与增强子功能相关的表观遗传标记。阐明这些非编码元件在这些细胞类型特异性基因组中的具体作用，对于我们理解SLE发病机制至关重要。
