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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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Chromatin Boundaries Separated by Repeat-Associated CTCF Binding in Rodents(A) A B2-associated CTCF-binding event separates the ApoA cluster from downstream genes on mouse chromosome 9 (top blue track). Active transcription is reflected both by H2AK5ac occupancy in mouse liver (bottom green track) and in direct sequencing of mouse liver mRNA by gene name shading (red is silent; green is active) (Mortazavi et al., 2008).(B) Heat map representation of H2AK5ac chromatin domains flanked by CTCF binding that is shared between all five species (five-way), mouse unique and repeat-associated (mouse RABs), repeat-associated and shared between mouse and rat (mouse and rat shared RABs), and not within the previous categories (all other).(C) Violin plots represent gene expression differences (Manhattan distances) between H2AK5ac and CTCF defined chromatin domains for different gene pair categories.See also Figure S6.
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fig6: Chromatin Boundaries Separated by Repeat-Associated CTCF Binding in Rodents(A) A B2-associated CTCF-binding event separates the ApoA cluster from downstream genes on mouse chromosome 9 (top blue track). Active transcription is reflected both by H2AK5ac occupancy in mouse liver (bottom green track) and in direct sequencing of mouse liver mRNA by gene name shading (red is silent; green is active) (Mortazavi et al., 2008).(B) Heat map representation of H2AK5ac chromatin domains flanked by CTCF binding that is shared between all five species (five-way), mouse unique and repeat-associated (mouse RABs), repeat-associated and shared between mouse and rat (mouse and rat shared RABs), and not within the previous categories (all other).(C) Violin plots represent gene expression differences (Manhattan distances) between H2AK5ac and CTCF defined chromatin domains for different gene pair categories.See also Figure S6.

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)

Chromatin Boundaries Separated by Repeat-Associated CTCF Binding in Rodents(A) A B2-associated CTCF-binding event separates the ApoA cluster from downstream genes on mouse chromosome 9 (top blue track). Active transcription is reflected both by H2AK5ac occupancy in mouse liver (bottom green track) and in direct sequencing of mouse liver mRNA by gene name shading (red is silent; green is active) (Mortazavi et al., 2008).(B) Heat map representation of H2AK5ac chromatin domains flanked by CTCF binding that is shared between all five species (five-way), mouse unique and repeat-associated (mouse RABs), repeat-associated and shared between mouse and rat (mouse and rat shared RABs), and not within the previous categories (all other).(C) Violin plots represent gene expression differences (Manhattan distances) between H2AK5ac and CTCF defined chromatin domains for different gene pair categories.See also Figure S6.
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Related In: Results  -  Collection

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fig6: Chromatin Boundaries Separated by Repeat-Associated CTCF Binding in Rodents(A) A B2-associated CTCF-binding event separates the ApoA cluster from downstream genes on mouse chromosome 9 (top blue track). Active transcription is reflected both by H2AK5ac occupancy in mouse liver (bottom green track) and in direct sequencing of mouse liver mRNA by gene name shading (red is silent; green is active) (Mortazavi et al., 2008).(B) Heat map representation of H2AK5ac chromatin domains flanked by CTCF binding that is shared between all five species (five-way), mouse unique and repeat-associated (mouse RABs), repeat-associated and shared between mouse and rat (mouse and rat shared RABs), and not within the previous categories (all other).(C) Violin plots represent gene expression differences (Manhattan distances) between H2AK5ac and CTCF defined chromatin domains for different gene pair categories.See also Figure S6.
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