Functional signatures of evolutionarily young CTCF binding sites
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RESEARCH ARTICLE
Open Access
Functional signatures of evolutionarily young CTCF binding sites Dhoyazan Azazi1, Jonathan M. Mudge1, Duncan T. Odom2,3 and Paul Flicek1,2,4*
Abstract Background: The introduction of novel CTCF binding sites in gene regulatory regions in the rodent lineage is partly the effect of transposable element expansion, particularly in the murine lineage. The exact mechanism and functional impact of evolutionarily novel CTCF binding sites are not yet fully understood. We investigated the impact of novel subspecies-specific CTCF binding sites in two Mus genus subspecies, Mus musculus domesticus and Mus musculus castaneus, that diverged 0.5 million years ago. Results: CTCF binding site evolution is influenced by the action of the B2-B4 family of transposable elements independently in both lineages, leading to the proliferation of novel CTCF binding sites. A subset of evolutionarily young sites may harbour transcriptional functionality as evidenced by the stability of their binding across multiple tissues in M. musculus domesticus (BL6), while overall the distance of subspecies-specific CTCF binding to the nearest transcription start sites and/or topologically associated domains (TADs) is largely similar to musculuscommon CTCF sites. Remarkably, we discovered a recurrent regulatory architecture consisting of a CTCF binding site and an interferon gene that appears to have been tandemly duplicated to create a 15-gene cluster on chromosome 4, thus forming a novel BL6 specific immune locus in which CTCF may play a regulatory role. Conclusions: Our results demonstrate that thousands of CTCF binding sites show multiple functional signatures rapidly after incorporation into the genome. Keywords: CTCF, Gene regulation, Evolutionary genomics
Background Genetic differences within and between species predominantly lie in the noncoding sequence of the regulatory regions of the genome, whose function and significance largely remain poorly understood [1–3]. While interspecies comparisons of mammalian genomes have revealed that protein-coding genes have been subject to strong selective pressures [4], tissue-specific transcription factor binding diverges more frequently between species [5–8].
* Correspondence: [email protected] 1 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK 2 University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK Full list of author information is available at the end of the article
CCCTC-binding factor (CTCF) is a ubiquitously expressed 11 zinc-finger master genome organiser [9] shared between all vertebrates [10]. It plays a part in many basic cellular roles including transcriptional activation and repression [11, 12], X-inactivation [13], establishing 3D genome architecture [14], enhancer insulation [15], and alternative splicing [16]. The importance of these functions is illustrated by CTCF knockout being embryonic lethal [17] and tissue-specific conditional k
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