Unbalanced Placental Expression of Imprinted Genes in Human Intrauterine Growth Restriction

• Published in: Placenta (Eastbourne) Vol. 27; no. 6; pp. 540 - 549
• Main Authors: McMinn, J., Wei, M., Schupf, N., Cusmai, J., Johnson, E.B., Smith, A.C., Weksberg, R., Thaker, H.M., Tycko, B.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-06-2006; Elsevier
• Subjects: Adult; Biological and medical sciences; Blotting, Northern; Blotting, Southern; Embryology: invertebrates and vertebrates. Teratology; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genomic Imprinting; Humans; Imprinting; Intrauterine growth restriction; IUGR; MEG3; MEST; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oligonucleotide Array Sequence Analysis; PHLDA2; Placenta; Placenta - metabolism; Pregnancy; Proteins - genetics; Proteins - metabolism; RNA, Messenger - metabolism; MEG3; Intrauterine growth restriction; Placenta; IUGR; Imprinting; PHLDA2; MEST; Human; Fetal diseases; Vertebrata; Intrauterine growth retardation; Mammalia; Pregnancy disorders; Fetal membrane; Gene expression
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2005.07.004

Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene,
PHLDA2, to that from a paternally expressed imprinted gene,
MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the
PHLDA2/
MEST mRNA ratio in IUGR (
p
=
0.0001). Altered expression of
PHLDA2 and
MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini–Hochberg false discovery rate of 0.05, with increased expression of
PHLDA2 and decreased expression of
MEST,
MEG3,
GATM,
GNAS and
PLAGL1 in IUGR placentae. At lower significance, we found
IGF2 mRNA decreased and
CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in
MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (
LEP,
CRH,
HPGD,
INHBA), tissue growth (
IGF1), immune modulation (
INDO,
PSG-family genes), oxidative metabolism (
GLRX), vascular function (
AGTR1,
DSCR1) and metabolite transport (
SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.