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.
Highlights
The human placenta provides a critical interface between the maternal and fetal circulations during pregnancy
We showed HLX expression is primarily in proliferating cytotrophoblast cell types and in mesenchymal stem/stromal cells during placental development[25, 27] and that HLX expression decreases in human idiopathic fetal growth restriction[20]
With regard to homeobox gene DLX3, we showed its expression was localised to nuclei of proliferating villous and extravillous cytotrophoblast cells, as well as in nuclei within the syncytiotrophoblast layer in the human placenta[17]
Summary
The human placenta provides a critical interface between the maternal and fetal circulations during pregnancy Formation of this interface is controlled by growth factors, cytokines and nuclear transcription factors. Transcription factors play essential roles in regulating cell proliferation and differentiation and this is evident in the most important placental lineage; trophoblast cells[1,2,3,4]. Homeobox gene DLX4 functional studies revealed this gene was a regulator of trophoblast cell apoptosis and had a potential role in epithelial-mesenchymal transition[26, 30]. Whilst studies are progressing on growth factor regulation of homeobox genes and target gene identification in normal and pathological human placental development, our understanding of how external or environmental factors regulate homeobox gene expression in extraembryonic tissues, most likely via epigenetic mechanisms, is manifestly inadequate. The HOX family of genes are more likely to show tissue-specific DNA methylation profiles compared with non-developmentally essential genes[38]
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