Smith, G. C. S. | bioRxiv Science

bioRxiv2022

The human placenta exhibits a unique transcriptomic void

We have recently demonstrated that the human placenta exhibits a unique genomic architecture with an unexpectedly high mutation burden(Coorens et al. 2021) and it is also well recognized that the placenta uniquely expresses many genes(Gong et al. 2021). However, the placenta is relatively understudied in systematic comparisons of gene expression in different organs. The aim of the present study was to identify transcripts which were uniquely absent or depleted, comparing the placenta with 46 other human organs. Here we show that 40/46 of the other organs had no transcripts which were selectively depleted and that of the remaining six, the liver had the largest number with 26. In contrast, the term placenta had 762 depleted transcripts. Gene Ontology analysis of this depleted set highlighted multiple pathways reflecting known unique elements of placental physiology. However, analysis of term samples demonstrated massive over representation of genes involved in mitochondrial function (P=5.8x10-10), including PGC-1 - the master regulator of mitochondrial biogenesis, and genes involved in polyamine metabolism (P=2.1x10-4). We conclude that the term placenta exhibits a unique metabolic environment.

genomics↗

bioRxiv2021

Placental polyamines regulate acetyl-coA and histone acetylation in a sex-dependent manner

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.

physiology↗