Proteome‐Wide Profiling of Readers for DNA Modification

• Published in: Advanced science 2021-10, Vol.8 (19), p.e2101426-n/a
• Main Authors: Bai, Lin, Yang, Guojian, Qin, Zhaoyu, Lyu, Jiacheng, Wang, Yunzhi, Feng, Jinwen, Liu, Mingwei, Gong, Tongqing, Li, Xianju, Li, Zhengyang, Li, Jixi, Qin, Jun, Yang, Wenjun, Ding, Chen
• Format: Article
• Language: English
• Subjects: 5-Methylcytosine - analogs & derivatives; 5-Methylcytosine - metabolism; Animals; Cell cycle; Cytosine - analogs & derivatives; Cytosine - metabolism; Datasets; DNA - genetics; DNA - metabolism; DNA methylation; DNA Methylation - drug effects; DNA modification; Epigenesis, Genetic - genetics; epigenetic regulation; Epigenetics; Gene expression; Gene Expression Profiling - methods; Genomes; Humans; mass spectrometry; Mice; Mice, Inbred C57BL; Models, Animal; Physiology; Proteins; Proteome - metabolism; proteomics; Transcription Factors - metabolism
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202101426

DNA modifications, represented by 5‐methylcytosine (5mC), 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxylcytosine (5caC), play important roles in epigenetic regulation of biological processes. The specific recognition of DNA modifications by the transcriptional protein machinery is thought to be a potential mechanism for epigenetic‐driven gene regulation, and many modified DNA‐specific binding proteins have been uncovered. However, the panoramic view of the roles of DNA modification readers at the proteome level remains largely unclear. Here, a recently developed concatenated tandem array of consensus transcription factor (TF) response elements (catTFREs) approach is employed to profile the binding activity of TFs at DNA modifications. Modified DNA‐binding activity is quantified for 1039 TFs, representing 70% of the TFs in the human genome. Additionally, the modified DNA‐binding activity of 600 TFs is monitored during the mouse brain development from the embryo to the adult stages. Readers of these DNA modifications are predicted, and the hierarchical networks between the transcriptional protein machinery and modified DNA are described. It is further demonstrated that ZNF24 and ZSCAN21 are potential readers of 5fC‐modified DNA. This study provides a landscape of TF–DNA modification interactions that can be used to elucidate the epigenetic‐related transcriptional regulation mechanisms under physiological conditions. Modified‐transcription factor response elements (TFREs) are developed, which profile the binding activity of TFs at DNA modifications (5mC, 5hmC, and 5fC), covering 70% of the TFs in the genome. A landscape of TF–DNA modification interaction is provided and the epigenetic‐related transcriptional regulation mechanisms are elucidated under physiological conditions. Potential readers of 5fC‐modified DNA are demonstrated and validated.