Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated - PubMed (original) (raw)

Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated

Mun-Kit Choy et al. BMC Genomics. 2010.

Abstract

Background: DNA methylation can regulate gene expression by modulating the interaction between DNA and proteins or protein complexes. Conserved consensus motifs exist across the human genome ("predicted transcription factor binding sites": "predicted TFBS") but the large majority of these are proven by chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) not to be biological transcription factor binding sites ("empirical TFBS"). We hypothesize that DNA methylation at conserved consensus motifs prevents promiscuous or disorderly transcription factor binding.

Results: Using genome-wide methylation maps of the human heart and sperm, we found that all conserved consensus motifs as well as the subset of those that reside outside CpG islands have an aggregate profile of hyper-methylation. In contrast, empirical TFBS with conserved consensus motifs have a profile of hypo-methylation. 40% of empirical TFBS with conserved consensus motifs resided in CpG islands whereas only 7% of all conserved consensus motifs were in CpG islands. Finally we further identified a minority subset of TF whose profiles are either hypo-methylated or neutral at their respective conserved consensus motifs implicating that these TF may be responsible for establishing or maintaining an un-methylated DNA state, or whose binding is not regulated by DNA methylation.

Conclusions: Our analysis supports the hypothesis that at least for a subset of TF, empirical binding to conserved consensus motifs genome-wide may be controlled by DNA methylation.

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Figures

Figure 1

Figure 1

Datasets of genomic locations. Set 1: Predicted TFBS based on conserved consensus motifs for 106 transcription factor families (N = 3,749,417). Set 2: Random genomic locations (N = 20,982). Set 3: Predicted TFBS for 17 transcription factor families (N = 771,221). Set 4: Biologically proven TFBS (empirical TFBS by ChIP-seq) with conserved consensus motifs (N = 40,876).

Figure 2

Figure 2

Genome-wide conserved consensus motifs (predicted TFBS) are hyper-methylated in human hearts and sperm. Methylation scores were determined across the genome for hearts and sperm using BATMAN [21]. The profiles of these scores (A: hearts, B: sperm) were plotted against locations of conserved consensus motifs for 106 transcription factor families centred on the predicted TF binding site (based on co-ordinates obtained from the UCSC genome web browser: TFBS Conserved track; "set 1", N = 3,749,417 locations). Methylation profile at random genomic locations was analyzed as a negative control and reflects a "neutral" methylation pattern at these locations ("set 2", N = 20,982).

Figure 3

Figure 3

Predicted TFBS with conserved consensus motifs are hyper-methylated unless they are also biologically proven TFBS (empirical TFBS). Aggregate methylation profiles for predicted TFBS with conserved consensus motifs for a subset of 17 transcription factor families are hyper-methylated in hearts (A) and sperm (B) (N = 771,221); but hypo-methylated if they are also biologically proven TFBS (empirical TFBS by ChIP-seq; "set 4", N = 40,876) (C: hearts and D: sperm).

Figure 4

Figure 4

Predicted TFBS with conserved consensus motifs residing outside of CGI are hyper-methylated. Aggregate methylation profiles for predicted TFBS with conserved consensus motifs ("set 3") that reside in CGI (A: hearts, B: sperm), and outside of CGI (C: hearts, D: sperm) showing that conserved consensus motifs are hypo-methylated when within CGI but hyper-methylated when outside of CGI.

Figure 5

Figure 5

Empirical TFBS with conserved consensus motifs are hypo-methylated in CGI but have a neutral methylation pattern when outside of CGI in the heart. Methylation profiles for empirical TFBS with conserved consensus motifs ("set 4") that resided in CGI (A: hearts, B: sperm), and outside CGI (C: hearts, D: sperm).

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