Evolution of the mammalian transcription factor binding repertoire via transposable elements

Abstract

Identification of lineage-specific innovations in genomic control elements is critical for understanding transcriptional regulatory networks and phenotypic heterogeneity. We analyzed, from an evolutionary perspective, the binding regions of seven mammalian transcription factors (ESR1, TP53, MYC, RELA, POU5F1, SOX2, and CTCF) identified on a genome-wide scale by different chromatin immunoprecipitation approaches and found that only a minority of sites appear to be conserved at the sequence level. Instead, we uncovered a pervasive association with genomic repeats by showing that a large fraction of the bona fide binding sites for five of the seven transcription factors (ESR1, TP53, POU5F1, SOX2, and CTCF) are embedded in distinctive families of transposable elements. Using the age of the repeats, we established that these repeat-associated binding sites (RABS) have been associated with significant regulatory expansions throughout the mammalian phylogeny. We validated the functional significance of these RABS by showing that they are over-represented in proximity of regulated genes and that the binding motifs within these repeats have undergone evolutionary selection. Our results demonstrate that transcriptional regulatory networks are highly dynamic in eukaryotic genomes and that transposable elements play an important role in expanding the repertoire of binding sites.

Evolutionary direction of processed pseudogenes

“…It is preferable for the selection to rely on easy-to-use repeats like Alu to expand TFBMs, because the Alu elements are not only densely distributed in the genome, but may also be a better source of binding motifs than pseudogenes. A similar previous prediction that some repeats harbor better binding motifs than random promoter templates proved to be true (Bourque et al, 2008). In other words, for evolution, Alus provide a way to create numerous similar TFBMs in a short time through their insertion in the proximal upstream regions of genes and the inclusion of a few subsequent point mutations, if needed, to optimize the binding sites.…”

High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression

“…We expect that further study of more complex genomes with higher transposon contents, such as mammalian or plant genomes, will uncover even greater numbers of such instances. Additionally, our study focused very specifically on transposons providing promoters, but these elements have been shown to have the potential to also contribute TFBSs, enhancers, silencers, insulators, or microRNA target sites (Bourque et al 2008;Bourque 2009;Lindblad-Toh et al 2011;Lynch et al 2011). Overall, our observations underscore the potential of transposons as a powerful and versatile creative force in regulatory innovation.…”

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

“…Interestingly, TEs that were conserved at unusually high levels over hundreds of millions of years were reported to act as enhancers (Bejerano et al 2006;Santangelo et al 2007;Sasaki et al 2008;LindbladToh et al 2011;Lowe and Haussler 2012). Recently, a number of publications proposed that the spreading of copies from active TE classes can lead to rapid rewiring, affecting hundreds of genes whose expression is being altered as a consequence, and is caused by the action of additional transcription factors binding to those enhancers Bourque et al 2008;Feschotte 2008;Xie et al 2010;Lynch et al 2011;Rebollo et al 2012). This might even involve Alu elements in the form of Alu-derived miRNAs or non-miRNAs Hoffman et al 2013;Liang and Yeh 2013;Mandal et al 2013;Spengler et al 2014).…”