YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths

Jiebo Lin; Guankai Zhan; Jinfeng Liu; Yasen Maimaitiyiming; Zhiping Deng; Baohua Li; Kunhui Su; Jiafeng Chen; Siqi Sun; Wanlin Zheng; Xianghui Yu; Feng He; Xiaodong Cheng; Lingfang Wang; Bin Shen; Ziqin Yao; Xinquan Yang; Jian Zhang; Wentao He; Hengyu Wu; Hua Naranmandura; Kao-Jung Chang; Junxia Min; Jun Ma; Mikael Björklund; Peng-Fei Xu; Fudi Wang; Chih-Hung Hsu

doi:10.1093/nsr/nwad227

YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths

Natl Sci Rev. 2023 Aug 28;10(12):nwad227. doi: 10.1093/nsr/nwad227. eCollection 2023 Dec.

Authors

Jiebo Lin^{1

2}, Guankai Zhan^{1

2}, Jinfeng Liu^{1

2

3}, Yasen Maimaitiyiming^{1

2

4}, Zhiping Deng⁵, Baohua Li⁶, Kunhui Su^{1

2}, Jiafeng Chen^{1

2}, Siqi Sun^{1

2}, Wanlin Zheng^{7

8}, Xianghui Yu^{7

8}, Feng He^{2

7

8}, Xiaodong Cheng⁹, Lingfang Wang^{1

2

9}, Bin Shen¹⁰, Ziqin Yao^{3

11}, Xinquan Yang^{3

11}, Jian Zhang^{1

2}, Wentao He^{1

2}, Hengyu Wu^{1

2}, Hua Naranmandura⁴, Kao-Jung Chang¹², Junxia Min¹³, Jun Ma^{2

7

8}, Mikael Björklund^{14

15}, Peng-Fei Xu^{2

7}, Fudi Wang^{3

11}, Chih-Hung Hsu^{1

2}

Affiliations

¹ Women's Hospital, The Fourth Affiliated Hospital, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006.
² Institute of Genetics, International School of Medicine, Zhejiang University, Yiwu 322000.
³ The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058.
⁴ Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310000.
⁵ State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Virology and Biotechnology, Zhejiang Academy of Agricultural Sciences, Hangzhou 310000.
⁶ Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310000.
⁷ Women's Hospital, and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310000.
⁸ Zhejiang Provincial Key Lab of Genetic and Developmental Disorders, Hangzhou 310058.
⁹ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310000.
¹⁰ State Key Laboratory of Reproductive Medicine, Center for Global Health, Gusu School, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing 211166.
¹¹ The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001.
¹² Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217.
¹³ The First Affiliated Hospital, Institute of Translational Medicine, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310058.
¹⁴ Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining 314400.
¹⁵ University of Edinburgh Medical School, Biomedical Sciences, College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, EH8 9JZ.

Abstract

N⁶-methyladenosine (m⁶A) is a critical regulator in the fate of RNA, but whether and how m⁶A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m⁶A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m⁶A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m⁶A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m⁶A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

Keywords: RNA m6A modification; bifurcation role of YTHDF2; environmental stress and m6A regulation; fluorene-9-bisphenol (BHPF); programmed cell deaths.