Vitamin D stimulates multiple microRNAs to inhibit CRH and other pro-labor genes in human placenta.
Vitamin D stimulates multiple microRNAs to inhibit CRH and other pro-labor genes in human placenta.
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DOI：
10.1530/ec-18-0345
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发表时间：
2018-12
影响因子：
2.9
通讯作者：
Rosen T
中科院分区：
文献类型：
--
作者：
Wang B;Cruz Ithier M;Parobchak N;Yadava SM;Schulkin J;Rosen T
母亲维生素D缺乏与不良妊娠结局有关，包括自发性早产（SPB）。胎盘促肾上腺皮质激素释放激素（CRH）被认为是控制人类妊娠时间的时钟的一部分，母体血清水平升高预示着早产。在这项研究中，我们测试的假设，维生素D可以通过抑制CRH和其他促分娩介质有助于预防早产。维生素D的生物活性通过两种途径发生：非基因组和基因组反应，两者都涉及1，25-二羟基维生素D（1，25（OH）2D）的结合，维生素D的活性代谢物与维生素D受体（VDR）结合。通过染色质免疫沉淀测序（ChIP-seq），我们发现1，25（OH）2D刺激VDR与包括MIR 181 B2和MIR 26 B在内的多个miRNA基因结合，其成熟产物miR-181 b-5 p和miR-26 b-5 p分别靶向CRH和环氧合酶-2（考克斯-2）mRNA的3′-非翻译区（UTR）。我们进行了RT-qPCR分析，以验证成熟的miR-181 b-5 p和miR-26 b-5 p在足月人合胞体滋养层中的表达在1，25（OH）2D处理后增加。通过使用miRNA模拟物/抑制剂和荧光素酶报告基因测定进一步评估miR-181 b-5 p或miR-26 b-5 p介导的CRH或考克斯-2抑制。总之，这项研究确定了维生素D下调促分娩基因的新机制，并可能降低早产的风险。
Maternal vitamin D deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study, we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3′-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p- or miR-26b-5p-mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms by which vitamin D downregulates pro-labor genes and could lower the risk of preterm delivery.