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Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages.

Schmidt D, Schwalie PC, Wilson MD, Ballester B, Gonçalves A, Kutter C, Brown GD, Marshall A, Flicek P, Odom DT - Cell (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

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Colocalization of TFs with Chromatin Barriers, Related to Figure 5The fractions of regions bound by CTCF in mouse liver as well as Oct4 and Nanog in mouse ESCs (Marson et al., 2008) that are found to be at mouse liver H2AK5ac domain boundaries are shown. Open circles indicate Oct4 and Nanog binding events that are more than 1 kb away from a CTCF-binding event. As random controls we shifted CTCF binding randomly (Shifted CTCF) and selected a set of random genomic regions (Random regions).
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figs6: Colocalization of TFs with Chromatin Barriers, Related to Figure 5The fractions of regions bound by CTCF in mouse liver as well as Oct4 and Nanog in mouse ESCs (Marson et al., 2008) that are found to be at mouse liver H2AK5ac domain boundaries are shown. Open circles indicate Oct4 and Nanog binding events that are more than 1 kb away from a CTCF-binding event. As random controls we shifted CTCF binding randomly (Shifted CTCF) and selected a set of random genomic regions (Random regions).

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).


Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages.

Schmidt D, Schwalie PC, Wilson MD, Ballester B, Gonçalves A, Kutter C, Brown GD, Marshall A, Flicek P, Odom DT - Cell (2012)

Colocalization of TFs with Chromatin Barriers, Related to Figure 5The fractions of regions bound by CTCF in mouse liver as well as Oct4 and Nanog in mouse ESCs (Marson et al., 2008) that are found to be at mouse liver H2AK5ac domain boundaries are shown. Open circles indicate Oct4 and Nanog binding events that are more than 1 kb away from a CTCF-binding event. As random controls we shifted CTCF binding randomly (Shifted CTCF) and selected a set of random genomic regions (Random regions).
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Related In: Results  -  Collection

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figs6: Colocalization of TFs with Chromatin Barriers, Related to Figure 5The fractions of regions bound by CTCF in mouse liver as well as Oct4 and Nanog in mouse ESCs (Marson et al., 2008) that are found to be at mouse liver H2AK5ac domain boundaries are shown. Open circles indicate Oct4 and Nanog binding events that are more than 1 kb away from a CTCF-binding event. As random controls we shifted CTCF binding randomly (Shifted CTCF) and selected a set of random genomic regions (Random regions).
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

Show MeSH
Related in: MedlinePlus