Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire

Abstract

The life-cycle of Endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA Pol II followed by reverse transcription and re-integration into the host genome. While most ERVs are relics of ancient integration events, “young” proviruses competent for retrotransposition- found in many mammals but not humans-represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life-cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloguing the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.

Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes

“…A rapidly growing body of literature shows in different model systems Thompson et al 2016). Co-option of LTR sequences may have clear biological implications, as shown for human innate immunity (Chuong et al 2016), mammalian development (Chuong et al 2013;Lynch et al 2015;Nishihara et al 2016), evolution of mammalian gene regulatory networks (Xie et al 2010;Sundaram et al 2014), or RNA interference in mice (Flemr et al 2013).…”

“…These patterns are defined by transcriptional activation mediated by maternal or zygotic transcription factors and transcriptional repression. Multiple mechanisms can mediate retrotransposon recognition and silencing (for review, see Crichton et al 2014;Friedli and Trono 2015;Wolf et al 2015;Thompson et al 2016). Transcriptional silencing involves distinct histone modification patterns, such as the loss of "active" (e.g., acetylation or H3K4me3) and emergence of "repressive" histone marks (e.g., H3K9me2/3 or H3K27me3).…”

“…Retrotransposon amplification threatens genome integrity through insertional mutations and chromosomal aberrations; consequently, defensive mechanisms evolved that suppress retrotransposons (for review, see Crichton et al 2014). Retrotransposons, however, can also provide functional gene parts, such as promoters, enhancers, exons, terminators, or splice junctions (for review, see de Souza et al 2013;Gerdes et al 2016;Göke and Ng 2016;Thompson et al 2016). Retrotransposons thus explore the space where their mutagenic potential coexists with other occasional contributions to gene expression.…”

KRAB zinc finger proteins

“…TEs endow the genomes of their host species with binding sites for transcription factors, which can then contribute to species-restricted phenotypes (reviewed by Thompson et al, 2016). For instance, mammals generally produce amylase in the pancreas, yet primates can release this enzyme in saliva too, owing to the insertion upstream of the amylase coding sequence of a HERV-E LTR driving expression in the salivary glands (Samuelson et al, 1996;Ting et al, 1992).…”

“…Nevertheless, such transposable elements (TEs) kept being considered mostly as genetic threats in need of the strictest silencing, and were otherwise dismissed as purely selfish or junk DNA (Doolittle and Sapienza, 1980). However, the sequencing of the human genome at the dawn of the century changed this view, and it is increasingly recognized that some TEs are crucial components of transcriptional regulatory networks that play essential roles not only in the evolution but also the biology of most organisms (Garcia-Perez et al, 2016;Chuong et al, 2017;Thompson et al, 2016). Moreover, recent work indicates that a particular family of transcriptional regulatorsKrüppel-associated box domain zinc finger proteins (KRAB-ZFPs) -controls TEs in higher vertebrates and, as such, exerts key influences on the biology of these organisms, including humans.…”