Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses.
Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses.
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DOI：
10.1371/journal.pgen.1006883
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Inoue I
中科院分区：
文献类型：
--
作者：
Ito J;Sugimoto R;Nakaoka H;Yamada S;Kimura T;Hayano T;Inoue I
人内源性逆转录病毒（HERV）和其它长末端重复序列（LTR）型逆转录转座子（HERV/LTR）具有可能影响宿主基因转录的调控元件。我们基于ENCODE和Roadmap表观基因组学项目提供的97个转录因子（TF）的ChIP-Seq公开数据集，系统地鉴定和表征了这些调控元件。我们使用ChIP-Seq数据集确定了转录因子结合位点（TFBS），并鉴定了在HERV/LTR序列（HERV-TFBS）上观察到的TFBS。总体而言，确定了794，972个HERV-TFBS。随后，我们鉴定了“HERV/LTR共享调控元件（HSRE）”，其定义为HERV-TFBS中的TF结合基序，在HERV/LTR类型的大部分内共享。HSRE可能表明HERV/LTR的调节元件在插入之前就存在。我们确定了2，201个HSRE，包括354个HERV/LTR和84个TF的特定关联。聚类分析显示，HERV/LTR可以根据TF结合模式进行分组; HERV/LTR组与多能TF结合（例如，SOX 2、POU 5 F1和NANOG）、胚胎内胚层/中内胚层TF（例如，GATA 4/6、SOX 17和FOXA 1/2）、造血TF（例如，鉴定了SPI 1（PU 1）、GATA 1/2和TAL 1）和CTCF。HERV/LTRs的调控元件倾向于与参与免疫应答的基因邻近和/或三维相互作用，表明调控元件在控制免疫调节网络中起重要作用。此外，我们证明了LTR 7、LTR 5 B和LTR5_H内的亚组特异性TF结合，表明在HERV/LTR的基因组侵入期间发生调节元件的获得或丢失。最后，我们构建了dbHERV-REs，一个HERV/LTR调控元件的交互式数据库（http：//herv-tfbs.com/）。这项研究为理解HERV/LTRs对宿主转录的影响提供了基础信息，并为HERV/LTRs和祖先HERV的转录调控系统提供了见解。人类内源性逆转录病毒（human endogenous retroviruses，HERVs）是古老的外源性逆转录病毒及其在宿主生殖细胞中复制的后代的基因组“化石”。古代逆转录病毒及其后代的特征和进化动力学可以通过仔细研究当今的HERV来推断。我们基于97个TF的ChIP-Seq公开数据集系统地鉴定了HERV的调控元件。聚类分析显示，HERV/LTR可以通过TF结合模式分组;由多能TF（例如，SOX 2、POU 5 F1和NANOG）、胚胎内胚层/中内胚层TF（例如，GATA 4/6、SOX 17和FOXA 1/2）和造血TF（例如，SPI 1（PU 1）、GATA 1/2和TAL 1）。通过分析三维染色体相互作用，我们证明了HERV的调控元件倾向于与宿主免疫应答基因相互作用。我们进一步证明了LTR 7内调控元件的异质性; SOX 2，POU 5 F1和KLF 4结合位点在LTR 7的最年轻亚组中高度富集，该亚组在多能细胞中具有最高的转录活性。这表明该亚组获得了在宿主生殖细胞中有效复制的那些调节活性。最后，我们构建了dbHERV-REs，一个HERV/LTR调控元件的交互式数据库（http：//herv-tfbs.com/）。这项研究提供了深入了解HERVs的调控元件和HERVs对宿主基因的转录调节。
Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)-type retrotransposons (HERV/LTRs) have regulatory elements that possibly influence the transcription of host genes. We systematically identified and characterized these regulatory elements based on publicly available datasets of ChIP-Seq of 97 transcription factors (TFs) provided by ENCODE and Roadmap Epigenomics projects. We determined transcription factor-binding sites (TFBSs) using the ChIP-Seq datasets and identified TFBSs observed on HERV/LTR sequences (HERV-TFBSs). Overall, 794,972 HERV-TFBSs were identified. Subsequently, we identified “HERV/LTR-shared regulatory element (HSRE),” defined as a TF-binding motif in HERV-TFBSs, shared within a substantial fraction of a HERV/LTR type. HSREs could be an indication that the regulatory elements of HERV/LTRs are present before their insertions. We identified 2,201 HSREs, comprising specific associations of 354 HERV/LTRs and 84 TFs. Clustering analysis showed that HERV/LTRs can be grouped according to the TF binding patterns; HERV/LTR groups bounded to pluripotent TFs (e.g., SOX2, POU5F1, and NANOG), embryonic endoderm/mesendoderm TFs (e.g., GATA4/6, SOX17, and FOXA1/2), hematopoietic TFs (e.g., SPI1 (PU1), GATA1/2, and TAL1), and CTCF were identified. Regulatory elements of HERV/LTRs tended to locate nearby and/or interact three-dimensionally with the genes involved in immune responses, indicating that the regulatory elements play an important role in controlling the immune regulatory network. Further, we demonstrated subgroup-specific TF binding within LTR7, LTR5B, and LTR5_Hs, indicating that gains or losses of the regulatory elements occurred during genomic invasions of the HERV/LTRs. Finally, we constructed dbHERV-REs, an interactive database of HERV/LTR regulatory elements (http://herv-tfbs.com/). This study provides fundamental information in understanding the impact of HERV/LTRs on host transcription, and offers insights into the transcriptional modulation systems of HERV/LTRs and ancestral HERVs. Human endogenous retroviruses (HERVs) are genomic “fossils” of ancient exogenous retroviruses and their descendants that were replicated in host germ cells. The traits and evolutionary dynamics of ancient retroviruses and their descendants can be inferred by scrutinizing present-day HERVs. We systematically identified regulatory elements of HERVs based on publicly available datasets of ChIP-Seq of 97 TFs. Clustering analysis showed that HERV/LTRs can be grouped by the TF-binding patterns; HERV/LTR groups bounded by pluripotent TFs (e.g., SOX2, POU5F1, and NANOG), embryonic endoderm/mesendoderm TFs (e.g., GATA4/6, SOX17, and FOXA1/2), and hematopoietic TFs (e.g., SPI1 (PU1), GATA1/2, and TAL1) were identified. By analyzing the three-dimensional chromosomal interactions, we demonstrated that regulatory elements of HERVs tend to interact with host immune-response genes. We further demonstrated heterogeneities of regulatory elements within LTR7; SOX2, POU5F1, and KLF4-binding sites were highly enriched in the youngest subgroup of LTR7, which had the highest transcriptional activity in pluripotent cells. This suggests that the subgroup acquired those regulatory activities for efficient replication in the host germ cells. Finally, we constructed dbHERV-REs, an interactive database of HERV/LTR regulatory elements (http://herv-tfbs.com/). This study provides insights into regulatory elements of HERVs and transcriptional modulations of host genes by HERVs.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
11.8
作者：
Goode DK;Obier N;Vijayabaskar MS;Lie-A-Ling M;Lilly AJ;Hannah R;Lichtinger M;Batta K;Florkowska M;Patel R;Challinor M;Wallace K;Gilmour J;Assi SA;Cauchy P;Hoogenkamp M;Westhead DR;Lacaud G;Kouskoff V;Göttgens B;Bonifer C
通讯作者：
Bonifer C
DOI：
10.1038/nrg3454
发表时间：
2013-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.7
作者：
Hedges SB;Marin J;Suleski M;Paymer M;Kumar S
通讯作者：
Kumar S
影响因子：
3.7
作者：
Derrien T;Estellé J;Marco Sola S;Knowles DG;Raineri E;Guigó R;Ribeca P
通讯作者：
Ribeca P