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Functional diversity of CTCFs is encoded in their binding motifs.

Fang R, Wang C, Skogerbo G, Zhang Z - BMC Genomics (2015)

Bottom Line: Supported by transcriptomic, epigenomic and chromatin-interactomic data, we show that the functional diversity of the CTCF binding motifs is strongly associated with their GC content, CpG dinucleotide coverage and relative DNA methylation level at the 12th position of the motifs.Finally, we present evidences for a hypothetical model in which chromatin interactions between promoters and distal regulatory regions are likely mediated by CTCFs binding to sequences with high CpG.These results demonstrate the existence of definitive CTCF binding motifs corresponding to CTCF's diverse functions, and that the functional diversity of the motifs is strongly associated with genetic and epigenetic features at the 12th position of the motifs.

View Article: PubMed Central - PubMed

Affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. r3fang@eng.ucsd.edu.

ABSTRACT

Background: The CCCTC-binding factor (CTCF) has diverse regulatory functions. However, the definitive characteristics of the CTCF binding motif required for its functional diversity still remains elusive.

Results: Here, we describe a new motif discovery workflow by which we have identified three CTCF binding motif variations with highly divergent functionalities. Supported by transcriptomic, epigenomic and chromatin-interactomic data, we show that the functional diversity of the CTCF binding motifs is strongly associated with their GC content, CpG dinucleotide coverage and relative DNA methylation level at the 12th position of the motifs. Further analysis suggested that the co-localization of cohesin, the key factor in cohesion of sister chromatids, is negatively correlated with the CpG coverage and the relative DNA methylation level at the 12th position. Finally, we present evidences for a hypothetical model in which chromatin interactions between promoters and distal regulatory regions are likely mediated by CTCFs binding to sequences with high CpG.

Conclusion: These results demonstrate the existence of definitive CTCF binding motifs corresponding to CTCF's diverse functions, and that the functional diversity of the motifs is strongly associated with genetic and epigenetic features at the 12th position of the motifs.

No MeSH data available.


Related in: MedlinePlus

Expression of CTCF-linked genes. The distribution of associated gene types for the different CTCF binding sites is shown for all three cell types. Active genes are more likely to be linked with CTCF-A, compared with CTCF-B and CTCF-C binding sites. (“*” and “**” indicate P-value < 0.01and P-value < 0.001, respectively). The expression levels are showed in logarithmic transformation
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Fig2: Expression of CTCF-linked genes. The distribution of associated gene types for the different CTCF binding sites is shown for all three cell types. Active genes are more likely to be linked with CTCF-A, compared with CTCF-B and CTCF-C binding sites. (“*” and “**” indicate P-value < 0.01and P-value < 0.001, respectively). The expression levels are showed in logarithmic transformation

Mentions: To investigate the association between gene expression activity and the occupancy of CTCF binding sites, we used a set of histone modification data from the Broad Institute [22] available from the ENCODE project (Additional file 6: Table S2), in combination with counts of histone marks in the flanking regions of each CTCF binding site (Fig. 2, Fig. 3a). We observed that regions close to CTCF-A binding sites were highly enriched for chromatin features that have been associated with active regulatory genome elements. For example, an enrichment of H3K4me3 and H3K9ac is considered a strong indication of an active promoter [23, 24], and an enrichment of H3K27ac separates active from poised enhancers [25]. In contrast, the vicinity of CTCF-A sites were depleted of repressive chromatin marks, such as H3K27me3 [26]. We did not observed any significant enrichment of particular chromatin features in the vicinity of CTCF-B and CTCF-C binding sites. This pattern was even more pronounced for tissue specific CTCF binding sites (Additional file 7: Figure S3), in that tissue specific CTCF-A binding sites showed a higher frequency of active chromatin marks than constitutive CTCF-A binding sites (Wilcoxon-Rank-Sum test p-value = 0.037 and 0.012 for H3K27ac and H3K4me3).Fig. 2


Functional diversity of CTCFs is encoded in their binding motifs.

Fang R, Wang C, Skogerbo G, Zhang Z - BMC Genomics (2015)

Expression of CTCF-linked genes. The distribution of associated gene types for the different CTCF binding sites is shown for all three cell types. Active genes are more likely to be linked with CTCF-A, compared with CTCF-B and CTCF-C binding sites. (“*” and “**” indicate P-value < 0.01and P-value < 0.001, respectively). The expression levels are showed in logarithmic transformation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4552278&req=5

Fig2: Expression of CTCF-linked genes. The distribution of associated gene types for the different CTCF binding sites is shown for all three cell types. Active genes are more likely to be linked with CTCF-A, compared with CTCF-B and CTCF-C binding sites. (“*” and “**” indicate P-value < 0.01and P-value < 0.001, respectively). The expression levels are showed in logarithmic transformation
Mentions: To investigate the association between gene expression activity and the occupancy of CTCF binding sites, we used a set of histone modification data from the Broad Institute [22] available from the ENCODE project (Additional file 6: Table S2), in combination with counts of histone marks in the flanking regions of each CTCF binding site (Fig. 2, Fig. 3a). We observed that regions close to CTCF-A binding sites were highly enriched for chromatin features that have been associated with active regulatory genome elements. For example, an enrichment of H3K4me3 and H3K9ac is considered a strong indication of an active promoter [23, 24], and an enrichment of H3K27ac separates active from poised enhancers [25]. In contrast, the vicinity of CTCF-A sites were depleted of repressive chromatin marks, such as H3K27me3 [26]. We did not observed any significant enrichment of particular chromatin features in the vicinity of CTCF-B and CTCF-C binding sites. This pattern was even more pronounced for tissue specific CTCF binding sites (Additional file 7: Figure S3), in that tissue specific CTCF-A binding sites showed a higher frequency of active chromatin marks than constitutive CTCF-A binding sites (Wilcoxon-Rank-Sum test p-value = 0.037 and 0.012 for H3K27ac and H3K4me3).Fig. 2

Bottom Line: Supported by transcriptomic, epigenomic and chromatin-interactomic data, we show that the functional diversity of the CTCF binding motifs is strongly associated with their GC content, CpG dinucleotide coverage and relative DNA methylation level at the 12th position of the motifs.Finally, we present evidences for a hypothetical model in which chromatin interactions between promoters and distal regulatory regions are likely mediated by CTCFs binding to sequences with high CpG.These results demonstrate the existence of definitive CTCF binding motifs corresponding to CTCF's diverse functions, and that the functional diversity of the motifs is strongly associated with genetic and epigenetic features at the 12th position of the motifs.

View Article: PubMed Central - PubMed

Affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. r3fang@eng.ucsd.edu.

ABSTRACT

Background: The CCCTC-binding factor (CTCF) has diverse regulatory functions. However, the definitive characteristics of the CTCF binding motif required for its functional diversity still remains elusive.

Results: Here, we describe a new motif discovery workflow by which we have identified three CTCF binding motif variations with highly divergent functionalities. Supported by transcriptomic, epigenomic and chromatin-interactomic data, we show that the functional diversity of the CTCF binding motifs is strongly associated with their GC content, CpG dinucleotide coverage and relative DNA methylation level at the 12th position of the motifs. Further analysis suggested that the co-localization of cohesin, the key factor in cohesion of sister chromatids, is negatively correlated with the CpG coverage and the relative DNA methylation level at the 12th position. Finally, we present evidences for a hypothetical model in which chromatin interactions between promoters and distal regulatory regions are likely mediated by CTCFs binding to sequences with high CpG.

Conclusion: These results demonstrate the existence of definitive CTCF binding motifs corresponding to CTCF's diverse functions, and that the functional diversity of the motifs is strongly associated with genetic and epigenetic features at the 12th position of the motifs.

No MeSH data available.


Related in: MedlinePlus