Abstract
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.
Highlights
Transposable elements (TEs) are mobile genomic DNA sequences that occupy approximately half of the human genome and are capable of autonomous or non-autonomous replication [1]
Human endogenous retroviruses (HERVs) are genomic “fossils” of ancient exogenous retroviruses and their descendants that were replicated in host germ cells
We systematically identified regulatory elements of HERVs based on publicly available datasets of ChIP-Seq of 97 transcription factors (TFs)
Summary
Transposable elements (TEs) are mobile genomic DNA sequences that occupy approximately half of the human genome and are capable of autonomous or non-autonomous replication [1]. TEs have their own regulatory elements for transcription and replication [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24] Such TE-derived regulatory elements are abundant in the human genome and have various effects on transcriptional modulations of host genes as promoters, enhancers, and insulators [9,10,11,12,13,14,15, 25,26,27,28,29,30,31,32,33,34]. Several studies have suggested that TE insertions have contributed to the rewiring and evolution of regulatory networks by recruiting multiple genes into the same regulatory circuit [10,11,12,13,14,15, 33,34,35,36,37]
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