Human HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts  

作　　者：Haibin Zhu Qianlei Ren Ziyi Yan Shouying Xu Jiahao Luo Ximei Wu Chao Tang 

机构地区：[1]National Clinical Research Center for Child Health of the Children’s Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang 310052,China [2]Department of Obstetrics and Gynaecology,The First Affiliated Hospital of Zhejiang University School of Medicine,Hangzhou,Zhejiang 310003,China [3]Department of Pharmacology,School of Medicine,Zhejiang University,Hangzhou,Zhejiang 310058,China

出　　处：《Journal of Genetics and Genomics》2022年第4期350-363,共14页遗传学报（英文版）

基　　金：supported by Natural Science Foundation of Zhejiang Province (LY17H160023 to H.Z.);National Basic Research Program of China (973 Program, 2018YFC1004404 to X.W.);Starting Research Foundation from The Children’s Hospital,Zhejiang University School of Medicine (481);National Natural Science Foundation of China (31801207 to C.T.)

摘　　要：Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy.The transcription factor gene heart and neural crest derivatives expressed1(Hand1)promotes differentiation of mouse trophoblast giant cells.However,the role of HAND1 in human trophoblasts remains unknown.Here,we report that HAND1 inhibits human trophoblastic progesterone(P4)and estradiol(E2)from cholesterol through downregulation of the expression of steroidogenic enzymes,including aromatase,P450 cholesterol side-chain cleavage enzyme(P450 scc),and 3β-hydroxysteroid dehydrogenase type 1(3β-HSD1).Mechanically,although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter,it restrains transcription of P450 scc by upregulation of the methylation status of P450 scc gene promoter through its binding to ALKBH1,a demethylase.Unlike aromatase and P450 scc,HAND1 decreases 3β-HSD1 m RNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein Hu R.Finally,HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2.Thus,our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts,which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.

关 键 词：HAND1 TROPHOBLAST CHOLESTEROL STEROIDS 

分 类 号：R321[医药卫生—人体解剖和组织胚胎学]