Epigenomics: Deciphering non-coding variation with 3D epigenomics.
Epigenomics: Deciphering non-coding variation with 3D epigenomics.
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DOI：
10.1038/nrg.2016.161
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发表时间：
2016-12-13
期刊：
影响因子：
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通讯作者：
Burgess, Darren J
中科院分区：
文献类型：
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作者：
Burgess, Darren J
一种新类型的未被探索的调控元件，当它们中出现遗传变异时，可能需要考虑。Javierre等人。然后使用他们的数据集来解释来自GWAS的非编码变体。他们发现，造血性PIRS富含与血液相关特征和疾病相关的单核苷酸多态(SNPs)，但不包括非血液特征。这验证了数据集的生理学相关性和实用性，但表明来自其他组织的PCI-C数据将需要更广泛地应用于各种疾病。作者将PCI-C数据整合到生物信息学管道中，以优先处理与疾病相关的SNPs的可能目标基因，并将其应用于各种自身免疫性疾病，包括类风湿性关节炎、系统性红斑狼疮、克罗恩病和溃疡性结肠炎。他们优先考虑了2500个潜在的疾病相关基因。这些基因中的三分之三以前没有与疾病有关，包括受远程相互作用调控的基因，这些基因可能会被依赖于初级DNA序列接近的方法所遗漏。最后，作者将他们的目标基因组装成一个“自身免疫网络”，以供社区进一步分析。在他们的研究中，施密特等人。在21种不同的原始人体组织和细胞类型上进行了Hi-C。他们分析了每种组织类型的平均2.14亿条独特的染色体接触，注意到一些区域显示出特别高的局部接触频率，他们称之为频繁相互作用区域(FIRE)。Fire不同于先前定义的染色体结构域类型，如A/B隔间、拓扑相关结构域(TADS)和环，尽管它们一般发生在TADS的中心，参与TAD内的许多相互作用，并包含在A隔室活性染色质的更广泛区域内。进一步的分析，包括与组蛋白修饰和转录的整合，揭示了FIRE是高度组织类型依赖的，经常发生在细胞识别基因附近(并在转录上调节)，并与活性增强子的染色质特征基本重叠。事实上，这种重叠对于聚集性火焰(“超级火焰”)尤其强烈，其中几乎100%包含聚集性增强剂(“超级增强剂”)或标准增强剂。考虑到火灾可能的基因调控活动，Schmitt等人。评估疾病相关性，发现与影响被检查的特定细胞类型的疾病相关的SNPs的火灾被丰富。通过分析火灾对，可以将与疾病相关的SNPs与已知和新的目标基因联系起来。进一步探索火灾在疾病遗传学研究中的价值将是有趣的，例如，确定火灾接触的典型短距离(200 Kb)性质是否会允许常规地发现较长范围的监管事件。然而，FIRES对于研究调节多个靶基因的发育动态增强剂可能特别有价值。总体而言，这些研究提供了对非编码变体调节目标基因并最终调节疾病表型的机制的见解。它们还为未来的挖掘和采用提供了数据集和方法。这些论文只是联合发表在Cell Press和其他期刊上的约40项IHEC研究的子集，并可在网上获得。
a new type of unexplored regulatory element that may need to be considered when genetic variants occur in them. Javierre et al. then used their data sets to interpret non-coding variants from GWAS. They found that haematopoietic PIRs were enriched for single-nucleotide polymorphisms (SNPs) associated with blood-relevant traits and diseases, but not non-blood traits. This validates the physiological relevance and utility of the data sets but indicates that PCHi-C data from other tissues will be needed for broader application to diverse diseases. The authors integrated PCHi-C data into a bioinformatic pipeline to prioritize likely target genes of disease-associated SNPs and applied it to various autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, Crohn disease and ulcerative colitis. They prioritized> 2,500 potential disease-associated genes. Threequarters of these genes were not previously implicated in disease, including genes regulated by long-range interactions, which would have been missed by methods relying on proximity within the primary DNA sequence. Finally, the authors assembled their target genes into an ‘autoimmunity network’for further analysis by the community. In their study, Schmitt et al. carried out Hi-C across 21 diverse primary human tissues and cell types. Analysing an average of 214 million unique chromosome contacts per tissue type, they noticed that some regions displayed particularly high local contact frequencies, which they termed frequently interacting regions (FIREs). FIREs were distinct from previously defined types of chromosome domains such as A/B compartments, topologically associated domains (TADs) and loops, although in general they occurred towards the centre of TADs, partook in numerous intra-TAD interactions and were contained within broader regions of A-compartment active chromatin. Further analyses, including integration with profiles of histone modifications and transcription, revealed that FIREs are highly tissue-type-dependent, frequently occur near (and transcriptionally regulate) cell-identity genes and overlap substantially with chromatin features of active enhancers. Indeed, the overlap was particularly strong for clustered FIREs (‘super-FIREs’), of which almost 100% contained clustered enhancers (‘super-enhancers’) or standard enhancers. Given the likely gene-regulatory activity of FIREs, Schmitt et al. assessed disease relevance, finding that FIREs are enriched for SNPs associated with diseases that affect the particular cell types examined. Analysing pairs of FIREs allowed disease-relevant SNPs to be linked to known and novel target genes. It will be interesting to further explore the value of FIREs in disease genetic studies to determine, for example, whether the typically short-range (< 200 kb) nature of FIRE contacts will allow longer-range regulatory events to be routinely uncovered. However, FIREs might be particularly valuable for studying developmentally dynamic enhancers that regulate multiple target genes. Overall, the studies provide insights into the mechanisms by which non-coding variants regulate target genes and, ultimately, disease phenotypes. They also provide datasets and methodologies for future mining and adoption. The papers represent just a subset of the~ 40 IHEC studies that were coordinately published in Cell Press and other journals, and are available online.