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Long Non-Coding RNA ZEB2-AS1 Augments Activity of Trophoblast Cells and Prevents the Development of Recurrent Spontaneous Abortion in Mice Through EZH2-Mediated CST3 Inhibition

  • Reproductive Biology: Original Article
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Abstract

Recurrent spontaneous abortion (RSA) is the most common complication of pregnancy where reduced invasion of trophoblasts plays a major role. This work aimed to explore the effect of abnormally expressed long non-coding RNA (lncRNA) ZEB2-AS1 on the occurrence of RSA. Differentially expressed lncRNAs in trophoblast cells between healthy controls and patients with RSA were screened using the GEO database. Female CBA/J mice were allowed to mate with male DBA/2 mice to establish inbred mice with RSA. ZEB2-AS1 was poorly expressed in placental tissues and trophoblast cells in the condition of RSA. ZEB2-AS1 upregulation augmented proliferation, migration, and invasion of trophoblast cells in vitro. ZEB2-AS1 negatively regulated cystatin C (CST3) expression. Further overexpression of CST3 blocked the activity of trophoblast cells. ZEB2-AS1 recruited enhancer of EZH2 to the promoter region of CST3, which increased H3K27me3 modification to suppress CST3 expression. In vivo, overexpression of ZEB2-AS1 reduced embryo resorption rate and increased the weights of fetuses and placentas in mice with RSA. However, the protective roles of ZEB2-AS1 were blocked upon artificial silencing of EZH2 or upregulation of CST3. Taken together, this study demonstrates that ZEB2-AS1 enhances activity of trophoblast cells and prevents RSA development through reducing CST3 expression in an EZH2-dependent manner.

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Availability of Data and Material

The datasets generated and/or analyzed during the current study are not publicly available due to research design but are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China

    Na Yu, Mengyang Du & Shihua Bao

  2. Department of Gynecology Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China

    Xiaoyue Chen, Hui Li & Yinyan He

  3. Reproductive Medical Center, Department of Gynecology and Obstetrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, People’s Republic of China

    Yanqiu Wang

  4. Department of Obstetrics and Gynecology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215100, Jiangsu, People’s Republic of China

    Feizhou Jiang

Authors
  1. Na Yu
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  2. Xiaoyue Chen
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  3. Mengyang Du
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  4. Hui Li
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  5. Yanqiu Wang
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  6. Feizhou Jiang
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  7. Shihua Bao
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  8. Yinyan He
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Contributions

NY, XYC, and FZJ: study concepts, study design, experimental studies, manuscript preparation, and editing; MYD, HL, YQW, and SHB: experimental studies, manuscript preparation, and editing; NY and XYC: literature research, experiments work, and manuscript writing; YYH: data acquisition and statistical analysis. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Feizhou Jiang, Shihua Bao or Yinyan He.

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Ethics Approval

This study was ratified by the Animal Ethical Committee of Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University (Approval No. ks2085). All animal procedures were strictly adhered to the Guide for the Care and Use of Laboratory Animals (NIH, Bethesda, Maryland, USA).

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The authors declare no competing interests.

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Yu, N., Chen, X., Du, M. et al. Long Non-Coding RNA ZEB2-AS1 Augments Activity of Trophoblast Cells and Prevents the Development of Recurrent Spontaneous Abortion in Mice Through EZH2-Mediated CST3 Inhibition. Reprod. Sci. 29, 963–974 (2022). https://doi.org/10.1007/s43032-022-00857-7

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  • DOI: https://doi.org/10.1007/s43032-022-00857-7

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