Broadening our understanding of genetic risk for scleroderma/systemic sclerosis by querying the chromatin architecture surrounding the risk haplotypes.
Broadening our understanding of genetic risk for scleroderma/systemic sclerosis by querying the chromatin architecture surrounding the risk haplotypes.
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DOI：
10.1186/s12920-021-00964-5
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发表时间：
2021-04-24
影响因子：
2.7
通讯作者：
Jarvis JN
中科院分区：
文献类型：
--
作者：
Poppenberg KE;Tutino VM;Tarbell E;Jarvis JN
人类白细胞抗原(HL A)基因变异增加了硬皮病/系统性硬化症(SSC)的风险。然而，还有其他复制基因座也会导致SSc的遗传风险，目前尚不清楚这些非HLA基因座的遗传风险是否主要作用于血管系统、免疫系统、成纤维细胞或其他相关细胞类型。我们使用Cistrome数据库调查了11个复制的SSC相关基因座周围的表观遗传景观，以确定这些基因座上的SNP是否可能影响调控元件，以及它们是否可能影响特定的细胞类型。我们将11个重复的SNP定位到单倍型，并试图确定在这些单倍型上是否存在显著的H3K27ac和H3K4me1标记，这是增强子功能的表观遗传特征。我们询问了病理上相关的细胞类型：B细胞、内皮细胞、成纤维细胞、单核细胞和T细胞。然后，我们确定了原代T细胞中包含SSC风险单倍型的拓扑相关结构域(TADS)，以确定可能受SSC原因SNPs影响的全部基因。我们对TADS中的基因进行了基因本体论分析，以深入了解SSC因果SNPs可能影响的免疫功能。SSc相关单倍型的H3K4me1/H3K27ac标记在单核细胞中得到丰富(p值为 <； 0.01)。在B细胞、成纤维细胞和T细胞中发现了两种组蛋白标记中的一种。血管内皮细胞未见浓集。对TADS中包含风险单倍型的基因的本体论分析表明，TADS中的基因在转录调节、蛋白质结合、T淋巴细胞激活和免疫细胞增殖方面具有丰富的功能。所查询的11种非HLASSC风险单倍型在广泛的免疫细胞和成纤维细胞中高度富含H3K4me1/H3K27ac标记的调节元件。此外，在免疫细胞中，风险单倍型属于较大的染色质结构，其中包含调控与SSC发病相关的广泛免疫过程的基因。尽管血管系统在SSc病理生物学中的重要性已被广泛接受，但我们无法找到这些区域内皮细胞功能受遗传影响的证据。网上版载有补充材料，可在10.1186/s12920-021-00964-5查阅。
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. The online version contains supplementary material available at 10.1186/s12920-021-00964-5.
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影响因子：
16
作者：
Phanstiel, Douglas H.;Van Bortle, Kevin;Snyder, Michael P.
通讯作者：
Snyder, Michael P.
影响因子：
64.5
作者：
Gasperini, Molly;Hill, Andrew J.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
5.1
作者：
Katebi, Majid;Fernandez, Patricia;Chan, Edwin S. L.;Cronstein, Bruce N.
通讯作者：
Cronstein, Bruce N.
DOI：
10.1126/science.1222794
发表时间：
2012-09-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maurano MT;Humbert R;Rynes E;Thurman RE;Haugen E;Wang H;Reynolds AP;Sandstrom R;Qu H;Brody J;Shafer A;Neri F;Lee K;Kutyavin T;Stehling-Sun S;Johnson AK;Canfield TK;Giste E;Diegel M;Bates D;Hansen RS;Neph S;Sabo PJ;Heimfeld S;Raubitschek A;Ziegler S;Cotsapas C;Sotoodehnia N;Glass I;Sunyaev SR;Kaul R;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
3
作者：
Eden, Eran;Navon, Roy;Yakhini, Zohar
通讯作者：
Yakhini, Zohar