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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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Tandem Gene Pairs Separated by CTCF Differ More in Their Expression than Gene Pairs that Are Not Separated by CTCF(A) Exemplified tandem gene pairs that are separated by CTCF binding or not separated by CTCF (no). The CTCF-separated tandem gene pairs are further distinguished into the following three groups: (1) shared between the five mammals shown in (B) (five-way shared), (2) associated with lineage-specific repeats (repeat-associated, RAB), (3) all other CTCF-separated gene pairs (all other).(B) Violin plots represent gene expression difference distributions (Manhattan distance) per tandem gene pair group as explained in (A). Stars (∗) indicate p values compared to the no CTCF binding category that are smaller than 0.001 (wilcoxon rank-sum test).
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fig7: Tandem Gene Pairs Separated by CTCF Differ More in Their Expression than Gene Pairs that Are Not Separated by CTCF(A) Exemplified tandem gene pairs that are separated by CTCF binding or not separated by CTCF (no). The CTCF-separated tandem gene pairs are further distinguished into the following three groups: (1) shared between the five mammals shown in (B) (five-way shared), (2) associated with lineage-specific repeats (repeat-associated, RAB), (3) all other CTCF-separated gene pairs (all other).(B) Violin plots represent gene expression difference distributions (Manhattan distance) per tandem gene pair group as explained in (A). Stars (∗) indicate p values compared to the no CTCF binding category that are smaller than 0.001 (wilcoxon rank-sum test).

Mentions: To further assess the functional impact of SINE-driven CTCF-binding events on transcription and gene expression, we explored whether CTCF can act as a transcriptional insulator between tandem genes (Figure 7A). Tandem genes are transcribed by RNA polymerase in the same direction and have been shown to have more coherence in their relative gene expression than non-tandem-organized genes (Caron et al., 2001; Lercher et al., 2002). We collected mRNA sequencing data in livers of all studied species, identified the subset of tandem genes divided by at least one CTCF-binding event in each species, and further subdivided this set by whether the CTCF-binding event was shared, repeat associated, or neither. In all species, we observed statistically significant increases in gene expression differences between tandem genes divided by CTCF (Figure 7B). We did not find any significant effects of the presence or absence of M2 on transcriptional insulation (data not shown). Indeed, repeat-associated CTCF-binding events in mouse, rat, and dog serve to transcriptionally separate members of tandem gene pairs.


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)

Tandem Gene Pairs Separated by CTCF Differ More in Their Expression than Gene Pairs that Are Not Separated by CTCF(A) Exemplified tandem gene pairs that are separated by CTCF binding or not separated by CTCF (no). The CTCF-separated tandem gene pairs are further distinguished into the following three groups: (1) shared between the five mammals shown in (B) (five-way shared), (2) associated with lineage-specific repeats (repeat-associated, RAB), (3) all other CTCF-separated gene pairs (all other).(B) Violin plots represent gene expression difference distributions (Manhattan distance) per tandem gene pair group as explained in (A). Stars (∗) indicate p values compared to the no CTCF binding category that are smaller than 0.001 (wilcoxon rank-sum test).
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fig7: Tandem Gene Pairs Separated by CTCF Differ More in Their Expression than Gene Pairs that Are Not Separated by CTCF(A) Exemplified tandem gene pairs that are separated by CTCF binding or not separated by CTCF (no). The CTCF-separated tandem gene pairs are further distinguished into the following three groups: (1) shared between the five mammals shown in (B) (five-way shared), (2) associated with lineage-specific repeats (repeat-associated, RAB), (3) all other CTCF-separated gene pairs (all other).(B) Violin plots represent gene expression difference distributions (Manhattan distance) per tandem gene pair group as explained in (A). Stars (∗) indicate p values compared to the no CTCF binding category that are smaller than 0.001 (wilcoxon rank-sum test).
Mentions: To further assess the functional impact of SINE-driven CTCF-binding events on transcription and gene expression, we explored whether CTCF can act as a transcriptional insulator between tandem genes (Figure 7A). Tandem genes are transcribed by RNA polymerase in the same direction and have been shown to have more coherence in their relative gene expression than non-tandem-organized genes (Caron et al., 2001; Lercher et al., 2002). We collected mRNA sequencing data in livers of all studied species, identified the subset of tandem genes divided by at least one CTCF-binding event in each species, and further subdivided this set by whether the CTCF-binding event was shared, repeat associated, or neither. In all species, we observed statistically significant increases in gene expression differences between tandem genes divided by CTCF (Figure 7B). We did not find any significant effects of the presence or absence of M2 on transcriptional insulation (data not shown). Indeed, repeat-associated CTCF-binding events in mouse, rat, and dog serve to transcriptionally separate members of tandem gene pairs.

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