Canon Stroke and Vascular Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
BMC Med Genomics. 2021 Apr 24;14(1):114. doi: 10.1186/s12920-021-00964-5.
Genetic variants in the human leukocyte antigen (HLA) locus contribute to the risk for developing scleroderma/systemic sclerosis (SSc). However, there are other replicated loci that also contribute to genetic risk for SSc, and it is unknown whether genetic risk in these non-HLA loci acts primarily on the vasculature, immune system, fibroblasts, or other relevant cell types. We used the Cistrome database to investigate the epigenetic landscapes surrounding 11 replicated SSc associated loci to determine whether SNPs in these loci may affect regulatory elements and whether they are likely to impact a specific cell type.
We mapped 11 replicated SNPs to haplotypes and sought to determine whether there was significant enrichment for H3K27ac and H3K4me1 marks, epigenetic signatures of enhancer function, on these haplotypes. We queried pathologically relevant cell types: B cells, endothelial cells, fibroblasts, monocytes, and T cells. We then identified the topologically associated domains (TADs) that encompass the SSc risk haplotypes in primary T cells to identify the full range of genes that may be influenced by SSc causal SNPs. We used gene ontology analyses of the genes within the TADs to gain insight into immunologic functions that might be affected by SSc causal SNPs.
The SSc-associated haplotypes were enriched (p value < 0.01) for H3K4me1/H3K27ac marks in monocytes. Enrichment of one of the two histone marks was found in B cells, fibroblasts, and T cells. No enrichment was identified in endothelial cells. Ontological analyses of genes within the TADs encompassing the risk haplotypes showed enrichment for regulation of transcription, protein binding, activation of T lymphocytes, and proliferation of immune cells.
The 11 non-HLA SSc risk haplotypes queried are highly enriched for H3K4me1/H3K27ac-marked regulatory elements in a broad range of immune cells and fibroblasts. Furthermore, in immune cells, the risk haplotypes belong to larger chromatin structures encompassing genes that regulate a wide array of immune processes associated with SSc pathogenesis. Though importance of the vasculature in the pathobiology of SSc is widely accepted, we were unable to find evidence for genetic influences on endothelial cell function in these regions.
人类白细胞抗原（HLA）基因座中的遗传变异导致发生硬皮病/系统性硬化症（SSc）的风险增加。然而，还有其他已复制的基因座也对 SSc 的遗传风险有贡献，并且尚不清楚这些非 HLA 基因座中的遗传风险主要作用于血管、免疫系统、成纤维细胞还是其他相关细胞类型。我们使用 Cistrome 数据库来研究 11 个已复制的 SSc 相关基因座周围的表观基因组景观，以确定这些基因座中的 SNP 是否可能影响调节元件，以及它们是否可能影响特定的细胞类型。
我们将 11 个已复制的 SNP 映射到单倍型上，并试图确定这些单倍型上是否存在 H3K27ac 和 H3K4me1 标记（增强子功能的表观遗传标志）的显著富集。我们查询了病理相关的细胞类型：B 细胞、内皮细胞、成纤维细胞、单核细胞和 T 细胞。然后，我们确定了包含 SSc 风险单倍型的原发性 T 细胞中的拓扑关联域（TAD），以识别可能受 SSc 因果 SNP 影响的完整基因范围。我们使用 TAD 内基因的基因本体分析来深入了解可能受 SSc 因果 SNP 影响的免疫功能。
SSc 相关的单倍型在单核细胞中 H3K4me1/H3K27ac 标记富集（p 值<0.01）。在 B 细胞、成纤维细胞和 T 细胞中发现了一个或两个组蛋白标记的富集，但在内皮细胞中没有发现富集。包含风险单倍型的 TAD 内基因的本体论分析显示，转录调控、蛋白质结合、T 淋巴细胞激活和免疫细胞增殖的富集。
所查询的 11 个非 HLA SSc 风险单倍型在广泛的免疫细胞和成纤维细胞中高度富集 H3K4me1/H3K27ac 标记的调节元件。此外，在免疫细胞中，风险单倍型属于更大的染色质结构，包含调节与 SSc 发病机制相关的广泛免疫过程的基因。尽管血管在 SSc 的病理生物学中具有重要作用，但我们未能在这些区域发现遗传对内皮细胞功能的影响的证据。
