Abstract
Eukaryotic gene regulation is mediated by cis-regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis-regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis-regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis-regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing.This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
Highlights
Following Barbara McClintock’s foundational maize kernel experiments in which transposable elements (TEs) were first discovered [1], Davidson & Britten [2] postulated a possible role of repetitive sequences and Transposable element (TE) in gene regulation
Transcription factors with more binding locations in the genome had higher fractions of binding to TEs [6]. This increase in the number of TF-binding locations mediated by TEs could be associated with an increase in the TF’s gene target repertoire and broader impact on gene expression, the latter notion remains to be functionally assessed [13]. This supports the idea that TEs could contribute to coordinated regulation in the genome by spreading DNA substrate for TF binding across the genome [2]
It is likely that ancestral TEs lack complete and optimized binding motifs for an entire repertoire of TFs that would be required for overcoming epigenomic restriction in a given somatic tissue, and instead in some instances gain these motifs via neutral substitution
Summary
Following Barbara McClintock’s foundational maize kernel experiments in which transposable elements (TEs) were first discovered [1], Davidson & Britten [2] postulated a possible role of repetitive sequences and TEs in gene regulation. High-throughput genomic technologies (such as massively parallel reporter assays or CRISPR editing/activation/interference) for quantifying regulatory potential of specific sequences, deleting genomic regions or perturbing their function enable us to determine functional roles of TEs in gene regulation and genome organization. These technological advancements have led to a recent explosion of studies documenting TE contribution to gene regulation via various cis-regulatory modes, which we discuss here with a focus on mammalian gene regulation
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