title: Widespread contribution of transposable elements to the innovation of gene regulatory networks.
abstract: Transposable elements (TEs) have been shown to contain functional binding sites for certain transcription factors (TFs). However, the extent to which TEs contribute to the evolution of TF binding sites is not well known. We comprehensively mapped binding sites for 26 pairs of orthologous TFs in two pairs of human and mouse cell lines (representing two cell lineages), along with epigenomic profiles, including DNA methylation and six histone modifications. Overall, we found that 20% of binding sites were embedded within TEs. This number varied across different TFs, ranging from 2% to 40%. We further identified 710 TF-TE relationships in which genomic copies of a TE subfamily contributed a significant number of binding peaks for a TF, and we found that LTR elements dominated these relationships in human. Importantly, TE-derived binding peaks were strongly associated with open and active chromatin signatures, including reduced DNA methylation and increased enhancer-associated histone marks. On average, 66% of TE-derived binding events were cell type-specific with a cell type-specific epigenetic landscape. Most of the binding sites contributed by TEs were species-specific, but we also identified binding sites conserved between human and mouse, the functional relevance of which was supported by a signature of purifying selection on DNA sequences of these TEs. Interestingly, several TFs had significantly expanded binding site landscapes only in one species, which were linked to species-specific gene functions, suggesting that TEs are an important driving force for regulatory innovation. Taken together, our data suggest that TEs have significantly and continuously shaped gene regulatory networks during mammalian evolution.
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
authors.forename: Vasavi
authors.initials: V
authors.lastname: Sundaram
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA;
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA;
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
authors.forename: Daofeng
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Edge
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA; mpsnyder@stanford.edu twang@genetics.wustl.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA; mpsnyder@stanford.edu twang@genetics.wustl.edu.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004251:DNA Transposable Elements; D057890:Epigenomics; D019143:Evolution, Molecular; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D005810:Multigene Family; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D004251:DNA Transposable Elements; D014157:Transcription Factors