An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine

Guang Song, Guohua Wang, Ximei Luo, Ying Cheng, Qifeng Song, Jun Wan, Cedric Moore, Hongjun Song, Peng Jin, Jiang Qian () and Heng Zhu ()
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Guang Song: Johns Hopkins University School of Medicine
Guohua Wang: Harbin Institute of Technology
Ximei Luo: Harbin Institute of Technology
Ying Cheng: Emory University School of Medicine
Qifeng Song: Johns Hopkins University School of Medicine
Jun Wan: Johns Hopkins University School of Medicine
Cedric Moore: Johns Hopkins University School of Medicine
Hongjun Song: University of Pennsylvania
Peng Jin: Emory University School of Medicine
Jiang Qian: Johns Hopkins University School of Medicine
Heng Zhu: Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.

Date: 2021
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DOI: 10.1038/s41467-021-20950-w

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