Sirtuin1 is Required for Proper Trophoblast Differentiation and Placental Development in Mice

Overview

Journal Placenta

Publisher Elsevier

Specialties Gynecology & Obstetrics
Physiology
Reproductive Medicine

Date 2018 Feb 7

PMID 29405961

Citations 13

Authors

Kanaga Arul Nambi Rajan

Marwa Khater

Francesca Soncin

Donald Pizzo

Matteo Moretto-Zita

Jonathan Pham

Orysya Stus

Pooja Iyer

Veronique Tache

Louise C Laurent

Mana M Parast

Affiliations

Soon will be listed here.

Abstract

Introduction: Placental insufficiency, arising from abnormal trophoblast differentiation and function, is a major cause of fetal growth restriction. Sirtuin-1 (Sirt1) is a ubiquitously-expressed NAD-dependent protein deacetylase which plays a key role in numerous cellular processes, including cellular differentiation and metabolism. Though Sirt1 has been widely studied, its role in placentation and trophoblast differentiation is unclear.

Method: Sirt1-heterozygous mice were mated and evaluated at various points during embryogenesis. In situ hybridization and immunohistochemistry were used to further characterize the placental phenotype of Sirt1-null mice. Wild-type (WT) and Sirt1-null mouse trophoblast stem cell (TSC) lines were derived from e3.5 littermate blastocysts. These cells were then evaluated at various points following differentiation. Differentiation was evaluated by expression of lineage specific markers using qPCR and flow cytometry, as well as Matrigel invasion assays. Global gene expression changes were evaluated using microarray-based RNA profiling; changes in specific pathways were validated using qPCR and western blot.

Results: In the absence of Sirt1, both embryos and placentas were small, with placentas showing abnormalities in both the labyrinthine layer and junctional zone. Sirt1-null TSCs exhibited an altered phenotype in both undifferentiated and differentiated states, phenotypes which corresponded to changes in pathways relevant to both TSC maintenance and differentiation. Specifically, Sirt1-null TSC showed blunted differentiation, and appeared to be suspended in an Epcam trophoblast progenitor state.

Discussion: Our results suggest that Sirt1 is required for proper TSC differentiation and placental development.

Citing Articles

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KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.

Bi S, Huang L, Chen Y, Hu Z, Li S, Wang Y Nat Commun. 2024; 15(1):5602.

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Bi S, Tu Z, Chen D, Zhang S Front Endocrinol (Lausanne). 2023; 14:1229862.

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