Altered downstream target gene expression of the placental Vitamin D receptor in human idiopathic fetal growth restriction

Thy P.H. Nguyen, Hannah E.J. Yong, Tejasvy Chollangi, Shaun P. Brennecke, Susan J. Fisher, Euan M. Wallace, Peter R. Ebeling, Padma Murthi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDR siRNA-transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2 and TGFB3. TGFB3 was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3 was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth.

Original languageEnglish
Pages (from-to)182-190
Number of pages9
JournalCell Cycle
Volume17
Issue number2
DOIs
Publication statusPublished - 17 Jan 2018

Keywords

  • cell-cycle regulation
  • idiopathic fetal growth restriction
  • placenta
  • TGFB3
  • Vitamin D receptor

Cite this

@article{6506d89a4bd44262acc347d0aee46efb,
title = "Altered downstream target gene expression of the placental Vitamin D receptor in human idiopathic fetal growth restriction",
abstract = "Fetal growth restriction (FGR) affects up to 5{\%} of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDR siRNA-transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2 and TGFB3. TGFB3 was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3 was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth.",
keywords = "cell-cycle regulation, idiopathic fetal growth restriction, placenta, TGFB3, Vitamin D receptor",
author = "Nguyen, {Thy P.H.} and Yong, {Hannah E.J.} and Tejasvy Chollangi and Brennecke, {Shaun P.} and Fisher, {Susan J.} and Wallace, {Euan M.} and Ebeling, {Peter R.} and Padma Murthi",
year = "2018",
month = "1",
day = "17",
doi = "10.1080/15384101.2017.1405193",
language = "English",
volume = "17",
pages = "182--190",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Taylor & Francis",
number = "2",

}

Altered downstream target gene expression of the placental Vitamin D receptor in human idiopathic fetal growth restriction. / Nguyen, Thy P.H.; Yong, Hannah E.J.; Chollangi, Tejasvy; Brennecke, Shaun P.; Fisher, Susan J.; Wallace, Euan M.; Ebeling, Peter R.; Murthi, Padma.

In: Cell Cycle, Vol. 17, No. 2, 17.01.2018, p. 182-190.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Altered downstream target gene expression of the placental Vitamin D receptor in human idiopathic fetal growth restriction

AU - Nguyen, Thy P.H.

AU - Yong, Hannah E.J.

AU - Chollangi, Tejasvy

AU - Brennecke, Shaun P.

AU - Fisher, Susan J.

AU - Wallace, Euan M.

AU - Ebeling, Peter R.

AU - Murthi, Padma

PY - 2018/1/17

Y1 - 2018/1/17

N2 - Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDR siRNA-transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2 and TGFB3. TGFB3 was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3 was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth.

AB - Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDR siRNA-transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2 and TGFB3. TGFB3 was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3 was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth.

KW - cell-cycle regulation

KW - idiopathic fetal growth restriction

KW - placenta

KW - TGFB3

KW - Vitamin D receptor

UR - http://www.scopus.com/inward/record.url?scp=85041120103&partnerID=8YFLogxK

U2 - 10.1080/15384101.2017.1405193

DO - 10.1080/15384101.2017.1405193

M3 - Article

VL - 17

SP - 182

EP - 190

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 2

ER -