Transcription Factor PLAGL1 Is Associated with Angiogenic Gene Expression in the Placenta

Int J Mol Sci. 2020 Nov 6;21(21):8317. doi: 10.3390/ijms21218317.

Abstract

During pregnancy, the placenta is important for transporting nutrients and waste between the maternal and fetal blood supply, secreting hormones, and serving as a protective barrier. To better understand placental development, we must understand how placental gene expression is regulated. We used RNA-seq data and ChIP-seq data for the enhancer associated mark, H3k27ac, to study gene regulation in the mouse placenta at embryonic day (e) 9.5, when the placenta is developing a complex network of blood vessels. We identified several upregulated transcription factors with enriched binding sites in e9.5-specific enhancers. The most enriched transcription factor, PLAGL1 had a predicted motif in 233 regions that were significantly associated with vasculature development and response to insulin stimulus genes. We then performed several experiments using mouse placenta and a human trophoblast cell line to understand the role of PLAGL1 in placental development. In the mouse placenta, Plagl1 is expressed in endothelial cells of the labyrinth layer and is differentially expressed in placentas from mice with gestational diabetes compared to placentas from control mice in a sex-specific manner. In human trophoblast cells, siRNA knockdown significantly decreased expression of genes associated with placental vasculature development terms. In a tube assay, decreased PLAGL1 expression led to reduced cord formation. These results suggest that Plagl1 regulates overlapping gene networks in placental trophoblast and endothelial cells, and may play a critical role in placental development in normal and complicated pregnancies.

Keywords: ChIP-seq; PLAGL1; RNA-seq; blood vessel development; enhancers; gestational diabetes; placenta; transcription factors; tube formation.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endothelial Cells / metabolism
  • Female
  • Gene Expression
  • Gene Regulatory Networks
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / genetics
  • Placenta / blood supply*
  • Placenta / metabolism*
  • Placentation / genetics*
  • Pregnancy
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Trophoblasts / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • PLAGL1 protein, human
  • Plag1 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Proteins