ACVR2A promoter polymorphism rs1424954 in the Activin-A signaling pathway in trophoblasts

Abstract Introduction 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 ACVR2A (rs1424954 (A > G)) has previously been shown to be...

Full description

Saved in:
Bibliographic Details
Published in:Placenta (Eastbourne) 2015-04, Vol.36 (4), p.345-349
Main Authors: Thulluru, H.K, Michel, O.J, Oudejans, C.B.M, van Dijk, M
Format: Article
Language:English
Subjects:
Activin Receptors, Type II - antagonists & inhibitors
Activin Receptors, Type II - chemistry
Activin Receptors, Type II - genetics
Activin Receptors, Type II - metabolism
Activin-A
Activins - metabolism
ACVR2A
ACVR2B
Alleles
Cell Line
Down-Regulation
Exons
Female
Gene Expression Regulation, Developmental
Humans
Internal Medicine
Nodal
Nodal Protein - antagonists & inhibitors
Nodal Protein - genetics
Nodal Protein - metabolism
Obstetrics and Gynecology
Peptide Fragments - agonists
Peptide Fragments - antagonists & inhibitors
Peptide Fragments - genetics
Peptide Fragments - metabolism
Polymorphism, Single Nucleotide
Pre-eclampsia
Pre-Eclampsia - genetics
Pre-Eclampsia - metabolism
Pregnancy
Promoter Regions, Genetic
Recombinant Proteins - metabolism
RNA Interference
RNA, Small Interfering
Signal Transduction
Trophoblast
Trophoblasts - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Introduction 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 ACVR2A (rs1424954 (A > G)) has previously been shown to be significantly associated with pre-eclampsia. Methods The effects of this variant on ACVR2A expression and its function in the Activin-A signaling pathway were studied by transfections in SGHPL-5 extravillous trophoblasts followed by qRT-PCR. Results Here we show that the ACVR2A promoter susceptibility variant causes a downregulation of ACVR2A expression. We also provide evidence for transcription of a so-called PROMPT (PROMoter-uPstream-Transcript) in the opposite direction of ACVR2A , containing the polymorphism, and downregulated when the susceptibility allele is carried, which either shares the same promoter as ACVR2A or is a non-coding RNA that is able to enhance ACVR2A transcription. Furthermore, when the effect of the susceptibility variant is mimicked by knockdown of ACVR2A , physiologic concentrations of Activin-A cause a reduction in NODAL mRNA expression in the SGHPL-5 trophoblasts, indicative of a protective effect as reduction in NODAL 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 ACVR2B. Discussion 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 NODAL , associated with reduced trophoblast invasion and observed in pre-eclamptic placentas.
ISSN:0143-4004
1532-3102
DOI:10.1016/j.placenta.2015.01.010