Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses

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. © 2017 ito et al.