The nuclear receptor REV-ERBαrepresses the transcription ofgrowth/differentiation factor 10and15genes in rat endometrium stromal cells

Abstract

Cellular oscillators in the uterus play critical roles in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes, including growth/differentiation factor (Gdf)10 and Gdf15. The expression of Gdf10 and Gdf15 is significantly increased in the uterus during decidualization, but the mechanism underlying the regulation of Gdf gene expression in the uterus is poorly understood. Here, we focused on the function of the cellular oscillators in the expression of Gdf family by using uterine endometrial stromal cells (UESCs) isolated from pregnant Per2‐dLuc transgenic rats. A significant decline of Per2‐dLuc bioluminescence activity was induced in in vitro decidualized UESCs, and concomitantly the expression of canonical clock genes was downregulated. Conversely, the expression of Gdf10 and Gdf15 of the Gdf was upregulated. In UESCs transfected with Bmal1‐specific siRNA, in which Rev‐erbα expression was downregulated, Gdf10 and Gdf15 were upregulated. However, Gdf5, Gdf7, and Gdf11 were not significantly affected by Bmal1 silencing. The expression of Gdf10 and Gdf15 was enhanced after treatment with a REV‐ERB α antagonist in the presence or absence of progesterone. Chromatin immunoprecipitation‐PCR analysis revealed the inhibitory effect of REV‐ERB α on the expression of Gdf10 and Gdf15 in UESCs by recognizing their gene promoters. Collectively, our findings indicate that the attenuation of REV‐ERB α leads to an upregulation of Gdf10 and Gdf15 in decidual cells, in which cellular oscillators are impaired. Our results provide novel evidence regarding the functions of cellular oscillators regulating the expression of downstream genes during the differentiation of UESCs.

Recent advances in modulators of circadian rhythms: an update and perspective

“…Compound 21 also caused significant increases in the expression levels of growth/differentiation factor Growth and differentiation factor 10 (GDF10) and Growth and differentiation factor 15 (GDF15) in uterine endometrial stromal cells (UESCs). These results show that cellular oscillators may serve an important role of regulating the expression of downstream genes during the differentiation of UESCs 89 .…”

Estradiol-17β-Induced Changes in the Porcine Endometrial Transcriptome In Vivo

“…Another E2-specific and pregnancy-specific DEG, also related in tissue remodeling, is macrophage inhibitory cytokine-1 (MIC-1), also named growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β (TGFB) superfamily, known to be expressed at high levels in human placenta [69]. GDF15 has been reported to be involved in actin cytoskeleton reorganization and remodeling [70] and is necessary for the maintenance of pregnancy in humans [71] and rats [72]. Intriguingly, it has been suggested that GDF15 participates in placenta development via promoting trophoblast cell invasion [73].…”

Research progress on circadian clock genes in common abdominal malignant tumors (Review)

“…Working on night or rotating shifts is linked to a greatly increased risk for women to develop breast and ovarian cancer, and for men to develop prostate cancer ( 69 – 71 ). Clock genes contribute to the occurrence and development of tumors by regulating and interfering with oncogenes (c-myc), tumor-suppressor genes (P53 and P21), genes involved in the regulation of the cell cycle (cyclins A, B1 and D1, and WEE1 G2 checkpoint kinase) and vascular endothelial growth factor, as well as affecting the internal secretion pathway ( 72 – 81 ) ( Fig. 1 ).…”