YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths  

作　　者：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 

机构地区：[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 Ed

出　　处：《National Science Review》2023年第12期77-91,共15页国家科学评论（英文版）

基　　金：supported by the National Natural Science Foundation of China(31972883 and 32270620 to C.H.H.,31930057 to F.W.,31970757 to P.F.X.,82000155 to Y.M.);the Key Program of Natural Science Foundation of Zhejiang Province(LZ23C060001 to C.H.H.);the National Key Research and Development Program of China(2021YFC2700903 and2022YFC2704203 to C.H.H.);the National Key Research and Development Program of China(2018YFA0507802 to F.W.,2018YFA0800102 to F.H.,2021YFC2700403 to J.M.);the China Postdoctoral Science Foundation(2021M702877 to Y.M.)。

摘　　要：N6-methyladenosine(m^(6)A)is a critical regulator in the fate of RNA,but whether and how m^(6)A executes its functions in different tissues remains largely obscure.Here we report downregulation of a crucial m^(6)A 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 m^(6)A-gch1 for cardiomyocyte ferroptosis,and decreased YTHDF2-mediated m^(6)A-sting1 decay for caudal vein plexus(CVP)apoptosis.The two distinct YTHDF2-mediated m^(6)A 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.

关 键 词：RNA m^(6)A modification programmed cell deaths bifurcation role of YTHDF2 environmental stress and m^(6)A regulation fluorene-9-bisphenol(BHPF) 

分 类 号：R114[医药卫生—卫生毒理学]