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Development. 2017 Jun 1;144(11):1976-1987. doi: 10.1242/dev.148916. Epub 2017 Apr 28.

G9a controls placental vascular maturation by activating the Notch Pathway.

Author information

1
Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
2
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
4
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
5
Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
6
Heart & Stroke Richard Lewar Centre of Excellence, Toronto, Ontario M5S 3H2, Canada.
7
Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada paul.delgadoolguin@sickkids.ca.

Abstract

Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation, during which blood vessels elongate. However, the cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase G9a, also known as Ehmt2, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand owing to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Rbpj Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, G9A and RBPJ were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation.

KEYWORDS:

Ehmt2; Epigenetic regulators; G9a; Gene expression; Human; Intrauterine growth restriction; Mouse; Placental vascular development; Vascular maturation

PMID:
28455378
DOI:
10.1242/dev.148916
[Indexed for MEDLINE]
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