Abstract
Up to 30% of women experience early miscarriage due to impaired decidualization. For implantation to occur, the uterine endometrial stromal fibroblast-like cells must differentiate into decidual cells, but the genes required for decidualization have not been fully defined. Here, we show that Malignant Brain Tumor Domain-containing Protein 1 (MBTD1), a member of the polycomb group protein family, is critical for human endometrial stromal cell (HESC) decidualization. MBTD1 predominantly localized to HESCs during the secretory phase and the levels were significantly elevated during in vitro decidualization of both immortalized and primary HESCs. Importantly, siRNA-mediated MBTD1 knockdown significantly impaired in vitro decidualization of both immortalized and primary HESCs, as evidenced by reduced expression of the decidualization markers PRL and IGFBP1. Further, knockdown of MBTD1 reduced cell proliferation and resulted in G2/M cell cycle arrest in decidualizing HESCs. Although progesterone signaling is required for decidualization, MBTD1 expression was not affected by progesterone signaling; however, MBTD1 knockdown significantly reduced expression of the progesterone target genes WNT4, FOXOA1, and GREB1. Collectively, our data suggest that MBTD1 contributes to in vitro decidualization of HESCs by sustaining progesterone signaling. This work could have implications for designing diagnostic and therapeutic tools for recurrent pregnancy loss.
Highlights
30% of women experience early miscarriage due to defective decidualization
Malignant Brain Tumor Domain-containing Protein 1 (MBTD1) raw expression score was significantly reduced in the endometrium from women with recurrent implantation failure compared to healthy women (Figure 1B, GSE65102) (Lucas et al, 2016)
We found an increased number of MBTD1 stained cells in stroma of secretory phase endometrium compared to proliferative phase endometrium (Figure 1C)
Summary
30% of women experience early miscarriage due to defective decidualization. Estrogen action is inhibited in uterine epithelia, and endometrial stromal cell decidualization initiates. Polycomb group (PcG) proteins play important roles in development through their ability to modify histones and thereby control gene expression (Luo et al, 2013). The PcG protein malignant brain tumor domaincontaining protein 1 (MBTD1) regulates gene expression by controlling the chromatin remodeling process. Acting as histone modifiers, the PcG proteins regulate gene transcription through methyltransferase activity (Mills, 2010) and by modulating histone acetyltransferase activity of the NuA4/TIP60 complex (Jacquet et al, 2016). We demonstrate that MBTD1 is upregulated during decidualization and plays an important role in progesterone-driven human and mouse endometrial stromal cell decidualization
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