Research Papers: Pathology:

BMAL1 facilitates trophoblast migration and invasion via SP1-DNMT1/DAB2IP pathway in recurrent spontaneous abortion

Shang Li, Junyu Zhai, Jiansheng Liu, Yan Hong, Weixiu Zhao, Aimin Zhao, Kang Sun, Yanzhi Du and Zi-Jiang Chen _

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Oncotarget. 2017; 8:89451-89464. https://doi.org/10.18632/oncotarget.20702

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Shang Li1,2, Junyu Zhai1,2, Jiansheng Liu1,2, Yan Hong1,2, Weixiu Zhao4, Aimin Zhao4, Kang Sun1,2, Yanzhi Du1,2 and Zi-Jiang Chen1,2,3

1 Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

2 Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

3 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, Jinan, China

4 Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Correspondence to:

Zi-Jiang Chen, email:

Yanzhi Du, email:

Keywords: BMAL1, recurrent spontaneous abortion, trophoblast, migration and invasion, progesterone, Pathology Section

Received: April 11, 2017 Accepted: July 25, 2017 Published: September 07, 2017


The underlying mechanism about rhythms and epigenetics leading to aberrant trophoblast migration and invasion in recurrent spontaneous abortion (RSA) remains unknown. Brain and muscle ARNT-like protein 1 (BMAL1) is considered as a crucial role in fertility, and polymorphism of BMAL1 gene has been reported to be associated with risk of miscarriage. However, the functional role of BMAL1 in RSA is not fully understood. Previous study shows the descended expression of DNA 5′-cytosine-methyltransferases 1 (DNMT1) in the villous of early pregnancy loss. Thus, understanding of the regulation of DNMT1 expression may be of significance for the elucidation of the process of RSA. Using HTR-8/SVneo and JEG-3 cell lines, we certified the induction of specificity protein 1 (SP1) to DNMT1 and DAB2 interaction protein (DAB2IP), respectively, both of which further activated matrix metallo-proteinase 2/9 (MMP2/9), bringing out changes in trophoblast migration and invasion. Notably, BMAL1 functioned as a positive upstream factor of SP1 only in HTR-8/SVneo cells but not in JEG-3 cells, inducing SP1-DNMT1/DAB2IP pathway and facilitating migration and invasion of trophoblasts. In addition, progesterone might restore the down-regulation of BMAL1 and downstream pathway in a dose-dependent manner. Last but not least, the decreased abundance of BMAL1 was correlated positively with that of SP1, DNMT1, DAB2IP, MMP2 and MMP9 in human villous specimens of RSA. Our results demonstrate that the induction of BMAL1 to SP1 contributes to the expression of DNMT1 and DAB2IP, respectively, activating trophoblast migration and invasion. The deregulation of the BMAL1-mediated pathway in RSA can be rescued by progesterone.

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