Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity

Xiufei Chen; Wenjie Zhou; Ren-Hua Song; Shuang Liu; Shu Wang; Yujia Chen; Chao Gao; Chenxi He; Jianxiong Xiao; Lei Zhang; Tianxiang Wang; Peng Liu; Kunlong Duan; Zhouli Cheng; Chen Zhang; Jinye Zhang; Yiping Sun; Felix Jackson; Fei Lan; Yun Liu; Yanhui Xu; Justin Jong-Leong Wong; Pu Wang; Hui Yang; Yue Xiong; Tong Chen; Yan Li; Dan Ye

doi:10.1126/sciadv.abl5220

Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity

Sci Adv. 2022 Jan 28;8(4):eabl5220. doi: 10.1126/sciadv.abl5220. Epub 2022 Jan 26.

Authors

Xiufei Chen^{1

2}, Wenjie Zhou^{1

3}, Ren-Hua Song⁴, Shuang Liu⁵, Shu Wang⁶, Yujia Chen^{1

3}, Chao Gao^{1

3}, Chenxi He^{1

3}, Jianxiong Xiao^{1

3}, Lei Zhang¹, Tianxiang Wang^{1

3}, Peng Liu^{1

3}, Kunlong Duan^{1

3}, Zhouli Cheng^{1

3}, Chen Zhang^{1

3}, Jinye Zhang^{1

3}, Yiping Sun^{1

3}, Felix Jackson⁷, Fei Lan^{1

3}, Yun Liu⁸, Yanhui Xu¹, Justin Jong-Leong Wong⁴, Pu Wang^{1

3}, Hui Yang⁹, Yue Xiong¹⁰, Tong Chen⁶, Yan Li⁵, Dan Ye^{1

3

11}

Affiliations

¹ Huashan Hospital, Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
² Target Discovery Institute, NDM Research Building, Oxford Ludwig Institute of Cancer Research, Oxford University, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK.
³ Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ Epigenetics and RNA Biology Program, Centenary Institute, The University of Sydney, Camperdown 2050, Australia.
⁵ MOE Key Laboratory of Model Animals for Disease Study, Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing, China.
⁶ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
⁷ Department of Computer Science, University of Oxford, 15 Parks Rd, Oxford OX1 3QD, UK.
⁸ MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China.
⁹ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
¹⁰ Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.

Abstract

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.