RT Journal Article
SR Electronic
T1 Placental polyamines regulate acetyl-coA and histone acetylation in a sex-specific manner
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.09.447192
DO 10.1101/2021.06.09.447192
A1 Irving LMH Aye
A1 Sungsam Gong
A1 Giulia Avellino
A1 Roberta Barbagallo
A1 Francesca Gaccioli
A1 Benjamin J Jenkins
A1 Albert Koulman
A1 Andrew J Murray
A1 D Stephen Charnock-Jones
A1 Gordon CS Smith
YR 2021
UL http://biorxiv.org/content/early/2021/06/10/2021.06.09.447192.abstract
AB Fetal sex differences play an important role in the pathophysiology of several placenta-related pregnancy complications. We previously reported that the maternal circulating level of a polyamine metabolite was altered in a fetal sex-specific manner, and was associated with pre-eclampsia and fetal growth restriction. Here we show that placental polyamine metabolism is altered in these disorders and that polyamines influence widespread changes in gene expression by regulating the availability of acetyl-CoA which is necessary for histone acetylation. Sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding the enzyme spermine synthase in female placentas, as evidenced by biallelic expression of the gene in female trophoblasts. Polyamine depletion in primary human trophoblasts impairs glycolysis and mitochondrial metabolism resulting in decreased availability of acetyl-CoA and global histone hypoacetylation, in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA–sequencing identifies downregulation of progesterone biosynthetic pathways as a key target and polyamine depletion reduced progesterone release in male trophoblasts. Collectively, these findings suggest that polyamines regulate placental endocrine function through metabolic regulation of gene expression, and that sex differences in polyamine metabolism due to XCI escape may buffer the effects of placental dysfunction in pregnancy disorders.Competing Interest StatementThe authors have declared no competing interest.