A Novel Approach to Identify Enhancer lincRNAs by Integrating Genome, Epigenome, and Regulatome
A Novel Approach to Identify Enhancer lincRNAs by Integrating Genome, Epigenome, and Regulatome
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通过整合基因组、表观基因组和调节组来识别增强子 lincRNA 的新方法
DOI：
10.3389/fbioe.2019.00427
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发表时间：
2019-12-17
影响因子：
5.7
通讯作者：
Wu，Qiong
中科院分区：
文献类型：
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作者：
Liu，Hui;Jiang，Tiantongfei;Wu，Qiong
富含高H3K4me1和低H3K4me3信号的LincRNAs通常具有增强子样特征，称为增强子相关LincRNAs （LincRNAs）。ElincRNAs被认为是靶基因转录不可或缺的，在发育、信号事件甚至疾病中发挥重要作用。在这项研究中，我们开发了一个正则化回归模型，通过整合基因组、表观基因组和调控数据来识别elincRNAs。该方法在小鼠ESCs中的应用表明，除了众所周知的基本表观遗传特征H3K4me1和H3K4me3外，更多特异性的表观遗传特征，如高DNA甲基化，高H3K122ac和H3K36me3，有助于以最佳的准确性和精密度标记elincRNAs。最后，在小鼠ESCs中鉴定出3729个elincrna。此外，elincRNAs和典型lincRNAs表现出不同的基因组特征，其中elincRNAs具有较高的CGI富集度和较低的序列保守性。通过转录调控分析，我们发现elincRNAs受到NANOG、POU5F1、SOX2和ESRRB的显著调控，参与控制ES细胞状态的核心转录调控回路。功能富集分析进一步发现，elincRNAs倾向于调控特定的胚胎发育生物学过程。这些结果表明，这两种lincrna都具有特定的表观遗传和转录调控机制，并表现出不同的功能特征。总之，我们提出了一个可靠的计算模型来优先考虑新的elincRNAs，并描绘了小鼠ESCs中elincRNAs的图谱，这将有助于解析lncRNAs在哺乳动物发育和疾病中的功能作用。
LincRNAs enriched with high H3K4me1 and low H3K4me3 signals often have the enhancer-like features which are named as enhancer-associated lincRNAs (elincRNAs). ElincRNAs are considered to be indispensable for target gene transcription, which play important roles in development, signaling events, and even diseases. In this study, we developed a regularized regression model to identify elincRNAs by integrating the genomic, epigenomic, and regulatory data. Application of the proposed method to mouse ESCs reveals that besides the basic well-known epigenetic features H3K4me1 and H3K4me3, more specific epigenetic features, such as high DNA methylation, high H3K122ac, and H3K36me3 were contributed to mark elincRNAs with the best accuracy and precision. Finally, 3729 elincRNAs were identified in mouse ESCs. Furthermore, the elincRNAs and canonical lincRNAs exhibit distinct genomic features, and elincRNAs have the higher CGI enrichment and lower sequence conservation. Through the analysis of transcription regulation, we found that elincRNAs were significantly regulated by NANOG, POU5F1, SOX2 and ESRRB, and were involved in the core transcriptional regulatory circuitry controlling ES cell state Function enrichment analysis further discovered that elincRNAs tended to regulate specific embryonic development biological processes. These results indicated that these two types of lincRNAs had both specific epigenetic and transcriptional regulation mechanism and display distinct functional characters. In conclusion, we presented a credible computational model to prioritize novel elincRNAs, and depicted the atlas of elincRNAs in mouse ESCs, which would help dissect the function roles of lncRNAs during the mammalian development and diseases.