Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages.
Bottom Line: To gain insight into how these DNA elements are conserved and spread through the genome, we defined the full spectrum of CTCF-binding sites, including a 33/34-mer motif, and identified over five thousand highly conserved, robust, and tissue-independent CTCF-binding locations by comparing ChIP-seq data from six mammals.We discovered fossilized repeat elements flanking deeply conserved CTCF-binding regions, indicating that similar retrotransposon expansions occurred hundreds of millions of years ago.Repeat-driven dispersal of CTCF binding is a fundamental, ancient, and still highly active mechanism of genome evolution in mammalian lineages.
Affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.Show MeSH
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Mentions: To assess the functional impact of SINE-driven CTCF-binding events on chromatin, we explored CTCF's known role as a barrier element that divides chromatin domains (Cuddapah et al., 2009; Xie et al., 2007). We reasoned that genomic locations where CTCF plays a functional role in separating chromatin domains would show distinct changes in histone modifications to either side of the CTCF-binding event. We therefore profiled the genome-wide location of histone 2A lysine 5 acetylation (H2AK5ac) (Cuddapah et al., 2009) and directly compared these data with matched CTCF occupancy data. This analysis identified hundreds of regions of abrupt changes in active chromatin demarcated by CTCF binding, consistent with CTCF's role as a barrier element and representing almost 5% of CTCF-binding events. Negative controls, such as unrelated TFs and random regions, showed only background level association with H2AK5ac in liver (Figure S6). In mouse, approximately 25% of CTCF chromatin boundaries were found to be associated with repetitive element expansion. For example, in mouse a CTCF-binding event found within a B2 SINE represented the boundary between the highly transcribed, liver-specific ApoA cluster of genes and the neighboring genes downstream on chromosome 9 (Figure 6A).
Affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.