N6-Methyladenine DNA Modification in the Human Genome

Mol Cell. 2018 Jul 19;71(2):306-318.e7. doi: 10.1016/j.molcel.2018.06.015.

Chuan-Le Xiao ¹, Song Zhu ², Minghui He ³, De Chen ², Qian Zhang ⁴, Ying Chen ⁵, Guoliang Yu ⁶, Jinbao Liu ⁷, Shang-Qian Xie ⁵, Feng Luo ⁸, Zhe Liang ⁹, De-Peng Wang ⁶, Xiao-Chen Bo ¹⁰, Xiao-Feng Gu ¹¹, Kai Wang ¹², Guang-Rong Yan ¹³

Affiliations

1 Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; College of Plant Protection, Hunan Agricultural University, Changsha 410128, China.
2 Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
3 CookGene Biosciences Center, Guangzhou 510320, China.
4 Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
5 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
6 Grandomics Biosciences, Beijing 102206, China.
7 Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
8 School of Computing, Clemson University, Clemson, SC 29634-0974, USA.
9 Department of Biological Sciences, National University of Singapore, 117543 Singapore, Singapore.
10 Dapartment of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: [email protected].
11 Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China. Electronic address: [email protected].
12 Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: [email protected].
13 Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China; Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: [email protected].

PMID: 30017583 DOI: 10.1016/j.molcel.2018.06.015

Abstract

DNA N⁶-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in the human genome, and we cataloged 881,240 6mA sites accounting for ∼0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. DNA 6mA and N⁶-demethyladenine modification in the human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompanied by decreased N6AMT1 and increased ALKBH1 levels, and downregulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis.

Keywords

6mA; cancer; demethylase; human genome; m6A; methylation; methyltransferase.

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