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Type: Journal article
Title: Increased methylation and decreased expression of homeobox genes TLX1, HOXA10 and DLX5 in human placenta are associated with trophoblast differentiation
Author: Novakovic, B.
Fournier, T.
Harris, L.
James, J.
Roberts, C.
Yong, H.
Kalionis, B.
Evain-Brion, D.
Ebeling, P.
Wallace, E.
Saffery, R.
Murthi, P.
Citation: Scientific Reports, 2017; 7(1):4523-1-4523-13
Publisher: Nature Publishing Group
Issue Date: 2017
ISSN: 2045-2322
Statement of
Boris Novakovic, Thierry Fournier, Lynda K. Harris, Joanna James, Claire T. Roberts, Hannah E. J. Yong, Bill Kalionis, Danièle Evain-Brion, Peter R. Ebeling, Euan M. Wallace, Richard Saffery and Padma Murthi
Abstract: Homeobox genes regulate embryonic and placental development, and are widely expressed in the human placenta, but their regulatory control by DNA methylation is unclear. DNA methylation analysis was performed on human placentae from first, second and third trimesters to determine methylation patterns of homeobox gene promoters across gestation. Most homeobox genes were hypo-methylated throughout gestation, suggesting that DNA methylation is not the primary mechanism involved in regulating HOX genes expression in the placenta. Nevertheless, several genes showed variable methylation patterns across gestation, with a general trend towards an increase in methylation over gestation. Three genes (TLX1, HOXA10 and DLX5) showed inverse gains of methylation with decreasing mRNA expression throughout pregnancy, supporting a role for DNA methylation in their regulation. Proteins encoded by these genes were primarily localised to the syncytiotrophoblast layer, and showed decreased expression later in gestation. siRNA mediated downregulation of DLX5, TLX1 and HOXA10 in primary term villous cytotrophoblast resulted in decreased proliferation and increased expression of differentiation markers, including ERVW-1. Our data suggest that loss of DLX5, TLX1 and HOXA10 expression in late gestation is required for proper placental differentiation and function.
Keywords: Cells, Cultured
Homeodomain Proteins
Proto-Oncogene Proteins
Transcription Factors
Chromosome Mapping
Cell Differentiation
DNA Methylation
Gene Expression Regulation
Gestational Age
Genes, Homeobox
Multigene Family
Homeobox A10 Proteins
Rights: © The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
DOI: 10.1038/s41598-017-04776-5
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