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

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.

Opposite Carcinogenic Effects of Circadian Clock Gene BMAL1

“…On the other hand, it has been reported that Bmal1 inhibits invasion in tongue squamous cell carcinoma cells and telomerase reverse transcriptase gene ( hTERT ) mediates Bmal1-driven sensitivity to an antineoplastic agent paclitaxel 44 . BMAL1 also promoted migration and invasion in an immortalized human extravillous trophoblast cell line HTR-8/SVneo 49 . In the present study, we used an invasive breast cancer cell line, MDA-MB-231, to analyse the effect of BMAL1 mutation on invasion.…”

RNA-sequencing analysis of umbilical cord plasma microRNAs from healthy newborns

“…Many of the genes that we identified as targets of these miRNA are believed to play a role in the preparation and development of the uterus in early pregnancy (TWIST1 [130], CDK6 [95], RUNX1 [138], CDK6 [95], MITF [130], HNRNPA2B1 [118] and BMP2 [123]), decidualisation (CDKN1A [153] and STAT3 [150]), implantation of the embryo (RECK [134], KRAS [122], CDH1 [155] and SMAD4 [160]) and the activation of the migration, invasion, proliferation and differentiation of the trophoblast (MAPK1 [125], MYC [135], TGFB [141], DAB2IP [103], RECK [133], SMAD7 [88] and STAT3 [149]). They continue to play roles during pregnancy…”

“…While CCNG2 [96] and FOXO4 [156] are downregulated in the placenta at full term. A number of these genes have been implicated in complications of preganacy including: miscarriage (VEGFA [147], DAB21P [103], CDKN1A [151,151,152], PTEN [124] and MDM2 [128]); preeclampsia (CD1C [105], CYP19A1 [102], VEGFA [147], CDKN1C [100,101], DAB2IP [104], CCNG2 [111] and GRB2 [116]); pre-term labour (RhoA [142,143]); gestational diabetes (CCNG2 [111,112], ITGA6 [113], RAB23 [113] and FOXO4 [158]); gestational trophoblastic disease (MDM2 [127]); male-specific neonatal encephalopathy (MECP2 [132]), neural tube defects (ITGA6 [113] and RAB23 [113]); Carpenter Syndrome (RAB23 [129]); intrahepatic cholestasis of pregnancy (PUM1 [139]); ectopic pregnancies (DKK3 [106]); and foetal conotruncal anomalies (MAPK1 [126].…”

Clinical and immunological aspects on recurrent pregnancy loss

“…Indeed, it has been shown that trophoblast dysfunction, due to compromised trophoblast infiltration and apoptosis, as well as multiple aberrant signal transduction pathways (64), could lead to adverse pregnancy outcomes, including uRPL (65). In detail, all the impaired pathways previously investigated in RPL trophoblast cells functions (including kisspeptin/GPR54 and PIBF/PR pathways, C4d and Bb, MBL, NOD1 and NOD2 via MAPK/p38 pathway, miR-27a-3p/USP25 axis, Fas and FasL, PKC protein, CCNA2, TWIST, Prototype and Chimera-Type Galectins, miR-520 and PARP1, BMAL1 via SP1-DNMT1/DAB2IP pathway, EIF5A1 via ARAF-mediated activation of integrin/ERK signaling pathway, Stathmin-1, peroxiredoxin2are) are linked to trophoblast migration, proliferation, invasion and apoptosis processes potentially relevant for RPL pathogenesis (64,(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78). Less is known about potential immunological impaired processes induced by trophoblast dysfunction.…”