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Functional diversity of CTCFs is encoded in their binding motifs.

ABSTRACT: 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.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.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.

SUBMITTER: Fang R

PROVIDER: S-EPMC4552278 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Functional diversity of CTCFs is encoded in their binding motifs.

Fang Rongxin R Wang Chengqi C Skogerbo Geir G Zhang Zhihua Z

BMC genomics 20150828

<h4>Background</h4>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.<h4>Results</h4>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 CTC ...[more]

PMID: 26315019

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Project description:BackgroundA large number of PROSITE patterns select false positives and/or miss known true positives. It is possible that--at least in some cases--the weak specificity and/or sensitivity of a pattern is due to the fact that one, or maybe more, functional and/or structural key residues are not represented in the pattern. Multiple sequence alignments are commonly used to build functional sequence patterns. If residues structurally conserved in proteins sharing a function cannot be aligned in a multiple sequence alignment, they are likely to be missed in a standard pattern construction procedure.ResultsHere we present a new procedure aimed at improving the sensitivity and/ or specificity of poorly-performing patterns. The procedure can be summarised as follows: 1. residues structurally conserved in different proteins, that are true positives for a pattern, are identified by means of a computational technique and by visual inspection. 2. the sequence positions of the structurally conserved residues falling outside the pattern are used to build extended sequence patterns. 3. the extended patterns are optimised on the SWISS-PROT database for their sensitivity and specificity. The method was applied to eight PROSITE patterns. Whenever structurally conserved residues are found in the surface region close to the pattern (seven out of eight cases), the addition of information inferred from structural analysis is shown to improve pattern selectivity and in some cases selectivity and sensitivity as well. In some of the cases considered the procedure allowed the identification of functionally interesting residues, whose biological role is also discussed.ConclusionOur method can be applied to any type of functional motif or pattern (not only PROSITE ones) which is not able to select all and only the true positive hits and for which at least two true positive structures are available. The computational technique for the identification of structurally conserved residues is already available on request and will be soon accessible on our web server. The procedure is intended for the use of pattern database curators and of scientists interested in a specific protein family for which no specific or selective patterns are yet available.

Dataset Information

Functional diversity of CTCFs is encoded in their binding motifs.

Publications

Functional diversity of CTCFs is encoded in their binding motifs.

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