Inhibitory role of REV-ERBα in the expression of bone morphogenetic protein gene family in rat uterus endometrium stromal cells

Jan 16, 2015American journal of physiology. Cell physiology

REV-ERBα reduces bone growth protein gene expression in rat uterine lining support cells

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Abstract

A significant decline in Per2-dLuc bioluminescence activity was observed in decidual cells during in vitro decidualization.

The expression of core Bmp genes Bmp2, Bmp4, Bmp6, and Bmp7 was upregulated during decidualization.
Downregulation of canonical clock genes occurred alongside the decline of Per2-dLuc activity.
Silencing of Bmal1 led to increased expression of Bmp2, Bmp4, and Bmp6, while Bmp1, Bmp7, and Bmp8a remained unaffected.
All Bmp genes showed enhanced expression after treatment with the REV-ERBα antagonist, though their rhythmic profiles varied.
REV-ERBα was identified as a transcriptional silencer for the Bmp gene family, binding to regions of the Bmp2 and Bmp4 promoters.

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Uterus circadian rhythms have been implicated in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes. Bone morphogenetic proteins (BMPs), having clock-controlled regulatory sites in their gene promoters, are expressed in the uterus during decidualization, but the regulation of the Bmp gene expression is poorly understood. The present study was designed to dissect the physiological roles of the uterus oscillators in the Bmp expression using the uterus endometrial stromal cells (UESCs) isolated from Per2-dLuc transgenic rats on day 4.5 of gestation. The in vitro decidualization of UESCs was induced by medroxyprogesterone acetate and 2-O-dibutyryl cAMP. A significant decline of Per2-dLuc bioluminescence activity was induced in decidual cells, and concomitantly, the expression of canonical clock genes was downregulated. Conversely, the expression of the core Bmp genes Bmp2, Bmp4, Bmp6, and Bmp7 was upregulated. In UESCs transfected with Bmal1-specific siRNA, in which Rev-erbα expression was downregulated, Bmp genes, such as Bmp2, Bmp4, and Bmp6 were upregulated. However, Bmp1, Bmp7, and Bmp8a were not significantly affected by Bmal1 silencing. The expression of all Bmp genes was enhanced after treatment with the REV-ERBα antagonist (SR8278), although their rhythmic profiles were differed from each other. The binding of REV-ERBα to the proximal regions of the Bmp2 and Bmp4 promoters was revealed by chromatin immunoprecipitation-PCR analysis. Collectively, these results indicate that the Bmp genes are upregulated by the attenuation of the cellular circadian clock; in particular, its core component REV-ERBα functions as a transcriptional silencer in the Bmp gene family.

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Inhibitory role of REV-ERBα in the expression of bone morphogenetic protein gene family in rat uterus endometrium stromal cells

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