Deciphering TAL effectors for 5-methylcytosine and 5-hydroxymethylcytosine recognition

• Published in: Nature communications Vol. 8; no. 1; pp. 901 - 9
• Main Authors: Zhang, Yuan, Liu, Lulu, Guo, Shengjie, Song, Jinghui, Zhu, Chenxu, Yue, Zongwei, Wei, Wensheng, Yi, Chengqi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/176/1988; 631/45/612/1229; Chromatin; Deoxyribonucleic acid; DNA; DNA methylation; Epigenetics; Eukaryotes; Gene sequencing; Genome editing; Genomes; Humanities and Social Sciences; multidisciplinary; Nucleotide sequence; Nucleotides; Proteins; Pyridine nucleotide reductase; Recognition; Science; Science (multidisciplinary); Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00860-6

DNA recognition by transcription activator-like effector (TALE) proteins is mediated by tandem repeats that specify nucleotides through repeat-variable diresidues. These repeat-variable diresidues form direct and sequence-specific contacts to DNA bases; hence, TALE–DNA interaction is sensitive to DNA chemical modifications. Here we conduct a thorough investigation, covering all theoretical repeat-variable diresidue combinations, for their recognition capabilities for 5-methylcytosine and 5-hydroxymethylcytosine, two important epigenetic markers in higher eukaryotes. We identify both specific and degenerate repeat-variable diresidues for 5-methylcytosine and 5-hydroxymethylcytosine. Utilizing these novel repeat-variable diresidues, we achieve methylation-dependent gene activation and genome editing in vivo; we also report base-resolution detection of 5hmC in an in vitro assay. Our work deciphers repeat-variable diresidues for 5-methylcytosine and 5-hydroxymethylcytosine, and provides tools for TALE-dependent epigenome recognition. Transcription activator-like effector proteins recognise specific DNA sequences via tandem repeats. Here the authors demonstrate TALEs can recognise the methylated bases 5mC and 5hmC, enabling them to detect epigenetic modifications.