Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity

• Published in: Science advances Vol. 8; no. 4; p. eabl5220
• Main Authors: Chen, Xiufei, Zhou, Wenjie, Song, Ren-Hua, Liu, Shuang, Wang, Shu, Chen, Yujia, Gao, Chao, He, Chenxi, Xiao, Jianxiong, Zhang, Lei, Wang, Tianxiang, Liu, Peng, Duan, Kunlong, Cheng, Zhouli, Zhang, Chen, Zhang, Jinye, Sun, Yiping, Jackson, Felix, Lan, Fei, Liu, Yun, Xu, Yanhui, Wong, Justin Jong-Leong, Wang, Pu, Yang, Hui, Xiong, Yue, Chen, Tong, Li, Yan, Ye, Dan
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 28.01.2022
• Subjects: Biomedicine and Life Sciences; Cell Biology; Genetics; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abl5220

DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPA N321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPA N321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA -mutated leukemia with DNA-hypomethylating agents. CEBPA interacts with DNMT3A and decreases its DNA accessibility and thus keeps DNMT3A activity “poised” near CEBPA binding sites.