Chromatin landscapes and genetic risk for juvenile idiopathic arthritis.
Chromatin landscapes and genetic risk for juvenile idiopathic arthritis.
复制标题
DOI：
10.1186/s13075-017-1260-x
复制
发表时间：
2017-03-14
影响因子：
4.9
通讯作者：
Jarvis JN
中科院分区：
文献类型：
--
作者：
Zhu L;Jiang K;Webber K;Wong L;Liu T;Chen Y;Jarvis JN
幼年特发性关节炎(JIA)患儿外周血细胞转录本有明显的转录异常，提示转录调控功能受损。为了更好地理解这一现象，我们研究了已知的JIA遗传风险基因座，其中大部分位于非编码区，在基因组范围内转录受到调控和协调。我们检测了人类中性粒细胞和CD4初级T细胞，以确定位于这些风险基因座内的基因和功能元件。我们分析了RNA测序(RNA-Seq)数据、H3K27ac和H3K4me1染色质免疫沉淀测序(ChIP-Seq)数据，以及先前发表的染色质相互作用分析(Chia-PET)数据，以表征已知的JIA相关风险基因座内的染色质景观。在中性粒细胞和原代CD4+T细胞中，大多数JIA相关的连锁不平衡(LD)块含有H3K27ac和/或H3K4me1标记。这些LD区块也是一小群转录因子的结合位点，特别是在中性粒细胞中。此外，这些区域在中性粒细胞中显示了丰富的内含子和基因间转录。在中性粒细胞中，未经治疗的JIA患者和健康儿童之间差异表达的基因中没有一个位于JIA风险LD区块内。在CD4+T细胞中，CHIA-PET数据显示，包括HLA-DQA1、HLA-DQB2、TRAF1和IRF1在内的多个基因与LD区域内的远距离相互作用区相关。这些发现表明，在JIA中观察到的异常转录控制与遗传风险有关。此外，这些发现表明，在复杂的基因组/染色质景观中识别实际的因果变异是一项挑战。本文的在线版本(doi：10.1186/s13075-017-1260-x)包含补充材料，授权用户可以使用。
The transcriptomes of peripheral blood cells in children with juvenile idiopathic arthritis (JIA) have distinct transcriptional aberrations that suggest impairment of transcriptional regulation. To gain a better understanding of this phenomenon, we studied known JIA genetic risk loci, the majority of which are located in non-coding regions, where transcription is regulated and coordinated on a genome-wide basis. We examined human neutrophils and CD4 primary T cells to identify genes and functional elements located within those risk loci. We analyzed RNA sequencing (RNA-Seq) data, H3K27ac and H3K4me1 chromatin immunoprecipitation-sequencing (ChIP-Seq) data, and previously published chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) data to characterize the chromatin landscapes within the known JIA-associated risk loci. In both neutrophils and primary CD4+ T cells, the majority of the JIA-associated linkage disequilibrium (LD) blocks contained H3K27ac and/or H3K4me1 marks. These LD blocks were also binding sites for a small group of transcription factors, particularly in neutrophils. Furthermore, these regions showed abundant intronic and intergenic transcription in neutrophils. In neutrophils, none of the genes that were differentially expressed between untreated patients with JIA and healthy children were located within the JIA-risk LD blocks. In CD4+ T cells, multiple genes, including HLA-DQA1, HLA-DQB2, TRAF1, and IRF1 were associated with the long-distance interacting regions within the LD regions as determined from ChIA-PET data. These findings suggest that genetic risk contributes to the aberrant transcriptional control observed in JIA. Furthermore, these findings demonstrate the challenges of identifying the actual causal variants within complex genomic/chromatin landscapes. The online version of this article (doi:10.1186/s13075-017-1260-x) contains supplementary material, which is available to authorized users.