Cross-talk between site-specific transcription factors and DNA methylation states

Abstract

DNA methylation, which occurs predominantly at CpG dinucleotides, is a potent epigenetic repressor of transcription. Because DNA methylation is reversible, there is much interest in understanding the mechanisms by which it can be regulated by DNA-binding transcription factors. We discuss several models that, by incorporating sequence motifs, CpG density, and methylation levels, attempt to link the binding of a transcription factor with the acquisition or loss of DNA methylation at promoters and distal regulatory elements. Additional in vivo genome-wide characterization of transcription factor binding patterns and high-resolution DNA methylation analyses are clearly required for stronger support of each model.

Keywords: DNA Methylation; DNA-binding Protein; Epigenetics; Gene Regulation; Transcription Factors.

FIGURE 1.

The effect of site-specific factors on DNA methylation. A, site-specific factors, such as SP1, bind unmethylated DNA, preventing DNA methyltransferases from accessing the promoter or enhancer. B, site-specific factors, such as NR6A1, can recruit DNA methyltransferases to unmethylated DNA, resulting in CpG methylation (meCpG). C, site-specific factors such as PPARG, which do not have a CpG in their motifs, can bind between methylated CpGs within a methylated region, recruiting TET proteins that oxidize 5-methylcytosine and reverse DNA methylation. D, site-specific factors, perhaps ZNF proteins, bind methylated motifs, recruiting histone methyltransferases and other repressive machinery.

FIGURE 2.

Site-specific transcription factors containing CpG dinucleotides within their recognition motif. An analysis of HOMER v4.3 and FactorBook motif databases (78, 79) identified a small number of motifs having at least one CpG dinucleotide at a critical position. These included motifs bound by members of the ATF family (ATF1, ATF3), EGR1, members of the ETS family (ETS1, ELF1, ELK4, GABPA), SP1, the MYC family (MYC, MAX, NMYC, USF1, BHLHE40), ZBTB33, CRE-binding factors, HIF1A, NRF1, and members of the E2F family. Shown are examples of the motif for a member of each family that has a critical CpG in its recognition sequence. ChIP-seq data for ATF3, EGR1, ELF1, SP1, USF1, and ZBTB33 produced by the ENCODE consortium (77) was compared with whole genome bisulfite sequencing data (A. Blattler and P. J. Farnham, unpublished data); all data are from HCT116 colorectal cancer cells. On the right, the degree of DNA methylation of a region ±1500 from the center of each ChIP-seq peak is plotted for those TFs. In all cases, DNA methylation is absent from the center of the TF-binding sites. To determine the in vivo relationship between TF binding and DNA methylation, experiments such as this must be performed comparing ChIP-seq data with whole genome DNA methylation data in matched cell types.