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

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Barbagallo, Roberta 
Gaccioli, Francesca  ORCID logo

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.

Acetyl Coenzyme A, Acetylation, Female, Gene Expression, Histones, Humans, Male, Placenta, Polyamines, Pregnancy, Progesterone, Spermine, Trophoblasts
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Commun Biol
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Springer Science and Business Media LLC
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
The work was supported by a Centre for Trophoblast Research Next Generation Fellowship to Irving Aye and the NIHR Cambridge Biomedical Research Centre (BRC, United Kingdom; G1100221).