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Review
. 2020 Aug 13;12(8):884.
doi: 10.3390/v12080884.

Silencing and Transcriptional Regulation of Endogenous Retroviruses: An Overview

Franziska K Geis  1   2   3 , Stephen P Goff  1   2   3
Affiliations
Review

Silencing and Transcriptional Regulation of Endogenous Retroviruses: An Overview

Franziska K Geis et al. Viruses. .

Abstract

Almost half of the human genome is made up of transposable elements (TEs), and about 8% consists of endogenous retroviruses (ERVs). ERVs are remnants of ancient exogenous retrovirus infections of the germ line. Most TEs are inactive and not detrimental to the host. They are tightly regulated to ensure genomic stability of the host and avoid deregulation of nearby gene loci. Histone-based posttranslational modifications such as H3K9 trimethylation are one of the main silencing mechanisms. Trim28 is one of the identified master regulators of silencing, which recruits most prominently the H3K9 methyltransferase Setdb1, among other factors. Sumoylation and ATP-dependent chromatin remodeling factors seem to contribute to proper localization of Trim28 to ERV sequences and promote Trim28 interaction with Setdb1. Additionally, DNA methylation as well as RNA-mediated targeting of TEs such as piRNA-based silencing play important roles in ERV regulation. Despite the involvement of ERV overexpression in several cancer types, autoimmune diseases, and viral pathologies, ERVs are now also appreciated for their potential positive role in evolution. ERVs can provide new regulatory gene elements or novel binding sites for transcription factors, and ERV gene products can even be repurposed for the benefit of the host.

Keywords: ERV expression and diseases; co-option of ERV functions; endogenous retroviruses (ERV); transcriptional silencing; transposable elements.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Organization, structure and classification of transposable elements (TEs). (A) TEs can be divided into DNA transposons or retrotransposons. Retrotransposons are defined either as long-terminal repeat (LTR)-retrotransposons, such as endogenous retroviruses (ERVs) or non- LTR retrotransposons, like long interspersed elements (LINE) or short interspersed elements (SINE). (B) Genomic structures are shown for provirus, ERV, LINE and SINE. A full-lenth version of ERV is shown exemplary, but genomic organizations can vary. Abbreviations: Pol II: polymerase III; pA: poly (A) tail; UTR: untranslated region; ORF: open reading frame. (C) Classification of ERVs comprises three classes. Human ERVs are depicted in bold.
Figure 2
Figure 2
Histone-based silencing of mouse TEs. KRAB-zinc finger proteins (Zfps) bind to TEs, either to the primer binding site or at other specific binding sites in TE sequences, and recruit Trim28. Trim28 is sumoylated via Sumo2, which enhances Trim28 localization to TEs. The chromatin remodeler Smarcad1 uses its ATPase activity to additionally improve Trim28 affinity to TEs and interaction with Setdb1. Setdb1, a H3K9-specific methyltransferase, establishes heterochromatin by formation of the histone H3K9 trimethylation mark, and HP1 binds that mark. H3K9 trimethylation-based silencing can spread to neighboring gene regions. YY1 binds to LTR regions of TEs and promotes TRIM28 recruitment. The HUSH complex can induce silencing through interaction with Trim28/Setdb1 and formation of H3K9 trimethylation. The histone chaperone Chaf1a interacts with Kdm1a and Hdac2 to suppress transcription of class III ERVs and Chaf1 cooprerates with Trim28 to establish H3K9 trimethylation for silencing class I and II ERVs. The histone chaperone isoforms Asf1a and Asf1b help localizing Chaf1a to TEs.
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