Abstract
DNA methylation is an important epigenetic mechanism for gene regulation. The conventional view of DNA methylation is that DNA methylation could disrupt protein-DNA interactions and repress gene expression. Several recent studies reported that DNA methylation could alter transcription factors (TFs) binding sequence specificity in vitro. Here, we took advantage of the large sets of ChIP-seq data for TFs and whole-genome bisulfite sequencing data in many cell types to perform a systematic analysis of the protein-DNA methylation in vivo. We observed that many TFs could bind methylated DNA regions, especially in H1-hESC cells. By locating binding sites, we confirmed that some TFs could bind to methylated CpGs directly. The different proportion of CpGs at TF binding specificity motifs in different methylation statuses shows that some TFs are sensitive to methylation and some could bind to the methylated DNA with different motifs, such as CEBPB and CTCF. At the same time, TF binding could interactively alter local DNA methylation. The TF hypermethylation binding sites extensively overlap with enhancers. And we also found that some DNase I hypersensitive sites were specifically hypermethylated in H1-hESC cells. At last, compared with TFs’ binding regions in multiple cell types, we observed that CTCF binding to high methylated regions in H1-hESC were not conservative. These pieces of evidence indicate that TFs that bind to hypermethylation DNA in H1-hESC cells may associate with enhancers to regulate special biological functions.
Highlights
DNA methylation is one type of epigenetic modification that plays an important role in many biological processes, including development, and disease progression (Das and Singal, 2004; Schübeler, 2015; Ambrosi et al, 2017; Horvath and Raj, 2018; Koch et al, 2018; Ando et al, 2019)
We wondered whether these transcription factors (TFs) could bind to methylated DNA in vivo
We investigated the DNA methylation status of the DNA bound by the TFs
Summary
DNA methylation is one type of epigenetic modification that plays an important role in many biological processes, including development, and disease progression (Das and Singal, 2004; Schübeler, 2015; Ambrosi et al, 2017; Horvath and Raj, 2018; Koch et al, 2018; Ando et al, 2019). Due to a recent technological development, mapping DNA methylation on a whole genome-wide scale has become less costly and more timesaving. DNA Methylation and TFs sequence (Hu et al, 2013; Zhu et al, 2016; Kribelbauer et al, 2017; Wang et al, 2018). A recent large-scale in vitro survey on the interactions between proteins and methylated DNA sequences suggested that transcription factors (TFs) could change the sequence specificity with or without DNA methylation (Yin et al, 2017). There are two possible explanations for the observation that TFs do not interact with methylated DNA sequences consistent with the conventional motif in vivo in the previous studies. One possibility is the intrinsic property of TFs which avoid methylated DNA sequences in vivo. They do not interact with the methylated sequence in cells since there are no accessible methylated DNA sequences in most cells
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