Placental sex-dependent spermine synthesis regulates trophoblast gene expression through acetyl-coA metabolism and histone acetylation

Abstract

Placental function and dysfunction differ by sex but the mechanisms are unknown. Here we show that sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding spermine synthase (SMS). Female placental trophoblasts demonstrate biallelic SMS expression, associated with increased SMS mRNA and enzyme activity. Polyamine depletion in primary trophoblasts reduced glycolysis and oxidative phosphorylation resulting in decreased acetyl-coA availability and global histone hypoacetylation in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies progesterone biosynthesis as a target of polyamine regulated gene expression, and polyamine depletion reduced progesterone release in male trophoblasts. The effects of polyamine depletion can be attributed to spermine as SMS-silencing recapitulated the effects on energy metabolism, histone acetylation, and progesterone release. In summary, spermine metabolism alters trophoblast gene expression through acetyl-coA biosynthesis and histone acetylation, and SMS escape from X inactivation explains some features of human placental sex differences.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction

“…This is consistent with previous studies that have demonstrated an important role for spermine, a polyamine, in controlling trophoblast metabolism and demonstrated opposite associations between maternal circulating levels of a spermine metabolite and the risk of preeclampsia and FGR. 26 , 27 As both preeclampsia and FGR are major determinants of the global burden of disease, 28 , 29 mechanistic studies are required to better understand the commonalities and differences in the pathways leading to these two placentally related complications.…”

The Placenta: A Maternofetal Interface

“…One spermine metabolite, diacetylspermine, detected in maternal serum was further associated with an increased risk of PE and a reduced risk of FGR (57). Functional assays of trophoblasts revealed that placentas of male fetuses were more susceptible to polyamine depletion, which was associated with impaired mitochondrial energy metabolism, and decreased histone acetylation and progesterone synthesis (6). Moreover, genes that escape from XCI may be essential for placental function, since monosomy X has been recently shown to impair development and maturation of the STB and EVT and reduce placental hormone production in a trophoblast model derived from human-induced pluripotent stem cells carrying a single copy of the X chromosome (2).…”

“…Moreover, genes that escape from XCI may be essential for placental function, since monosomy X has been recently shown to impair development and maturation of the STB and EVT and reduce placental hormone production in a trophoblast model derived from human-induced pluripotent stem cells carrying a single copy of the X chromosome (2). Interestingly, variable expression of the paternal allele, maternal allele, or both alleles of an X-linked gene was noted across different locations in term placentas (98) and among single nuclei of isolated trophoblasts (6). How mosaic expression of X-linked genes affects trophoblast phenotypes and contributes to sexual dimorphism in placental function and pregnancy complications are questions that merit further study.…”

Ovarian aging: energy metabolism of oocytes

“…[322]. Additionally, depletion of polyamines in cells leads to glycolysis inhibition, suppression of the TCA cycle and OXPHOS, decreased levels of acetyl-CoA and histone acetylation, downregulation of mitochondrial metabolism genes, downregulation of TCA intermediates and OXPHOS activity, upregulation of stress signaling, and enhanced mitochondrial permeability [323,324]. For oocytes, the level of putrescine decreases with age and is one of the main factors for poor quality in the oocytes of aged mouse [325].…”