Abstract
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.
Highlights
Recurrent spontaneous abortion (RSA), used to be defined as three or more spontaneous consecutive abortions prior to 20 weeks of gestation, impacts approximately 1 % - 2 % of couples
We examined the effect of Brain and muscle ARNT-like protein 1 (BMAL1) on the migration of HTR-8/SVneo using a scratch-wound assay
A transwell assay was used finding out that BMAL1 small interfering RNA (siRNA) treatment markedly decreased the invasion of HTR-8/SVneo cells compared with cells treated with negative control (NC) siRNA (Figure 1E)
Summary
Recurrent spontaneous abortion (RSA), used to be defined as three or more spontaneous consecutive abortions prior to 20 weeks of gestation, impacts approximately 1 % - 2 % of couples. Some clinicians redefine RSA as two or more losses and this definition makes the percentage of RSA to 5 % [1, 2]. Abnormal embryonic karyotypes have been regarded as a major cause of RSA [3], such as trisomy, polyploidy or monosomy X arising de novo as a result of meiotic non-disjunction during gametogenesis. Several etiological factors account, such as parental chromosomal rearrangements, endocrine abnormalities, anatomical factors, immunologic www.impactjournals.com/oncotarget factors, infectious diseases, inherited thrombophilic disorders, etc. Molecular mechanisms still remain incompletely understood, especially with respect to the cases in which embryos are chromosomally normal
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