Human HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts

Haibin Zhu; Qianlei Ren; Ziyi Yan; Shouying Xu; Jiahao Luo; Ximei Wu; Chao Tang

doi:10.1016/j.jgg.2021.07.014

Volume 49 Issue 4

Apr. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(4): 350-363

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Human HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts

doi: 10.1016/j.jgg.2021.07.014

a National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China;
b Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China;
c Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China

Funds:

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

Received Date: 2021-04-07
Accepted Date: 2021-07-17
Rev Recd Date: 2021-07-11
Publish Date: 2022-04-30

Abstract

Abstract

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 expressed 1 (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 (P450scc), 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 P450scc by upregulation of the methylation status of P450scc gene promoter through its binding to ALKBH1, a demethylase. Unlike aromatase and P450scc, HAND1 decreases 3β-HSD1 mRNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein HuR. 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.
- HAND1,
- Trophoblast,
- Cholesterol,
- Steroids

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References(54)

References

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