ACVR2A promoter polymorphism rs1424954 in the Activin-A signaling pathway in trophoblasts. Issue 4 (April 2015)

• Record Type: Journal Article
• Authors: Thulluru, H.K.; Michel, O.J.; Oudejans, C.B.M.; van Dijk, M.
• Is Part Of: Placenta. Volume 36:Issue 4(2015:Apr.)
• Page Start: 345
• Page End: 349
• Publication Date: 2015-04
• Subjects: Placenta -- Periodicals; Reproduction -- Periodicals; Placenta -- Periodicals; Placenta -- Périodiques; Reproduction -- Périodiques; 612.63
• DOI: 10.1016/j.placenta.2015.01.010
• Languages: English
• ISSNs: 0143-4004

Abstract

<abstract xml:lang="en" abstract-type="author" id="abs0010"> <title id="sectitle0010">Abstract</title> <sec> <title id="sectitle0015">Introduction</title> <p id="abspara0010">Pre-eclampsia is a pregnancy-specific disorder and characterized by reduced trophoblast invasion and reduced spiral artery remodeling in the first trimester placenta. A polymorphism located in the promoter region of <italic>ACVR2A</italic> (rs1424954 (A > G)) has previously been shown to be significantly associated with pre-eclampsia.</p> </sec> <sec> <title id="sectitle0020">Methods</title> <p id="abspara0015">The effects of this variant on <italic>ACVR2A</italic> expression and its function in the Activin-A signaling pathway were studied by transfections in SGHPL-5 extravillous trophoblasts followed by qRT-PCR.</p> </sec> <sec> <title id="sectitle0025">Results</title> <p id="abspara0020">Here we show that the <italic>ACVR2A</italic> promoter susceptibility variant causes a downregulation of <italic>ACVR2A</italic> expression. We also provide evidence for transcription of a so-called PROMPT (PROMoter-uPstream-Transcript) in the opposite direction of <italic>ACVR2A</italic>, containing the polymorphism, and downregulated when the susceptibility allele is carried, which either shares the same promoter as <italic>ACVR2A</italic> or is a non-coding RNA that is able to enhance <italic>ACVR2A</italic> transcription. Furthermore, when the effect of the susceptibility variant is mimicked by knockdown of <italic>ACVR2A</italic>, physiologic concentrations of Activin-A cause a reduction in <italic>NODAL</italic> mRNA expression in the SGHPL-5 trophoblasts, indicative of a protective effect as reduction in <italic>NODAL</italic> expression is associated with an increase in trophoblast invasion. However, at pathologic levels of Activin-A, as found in pre-eclampsia, this effect is no longer seen, and we show this is potentially caused by a lack of downregulation of <italic>ACVR2B.</italic></p> </sec> <sec> <title id="sectitle0030">Discussion</title> <p id="abspara0025">The combined data suggest a double hit phenomenon in which the first hit, the promoter variant, together with the second hit, pathological levels of Activin-A, lead to high levels of <italic>NODAL</italic>, associated with reduced trophoblast invasion and observed in pre-eclamptic placentas.</p> </sec> </abstract>