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Data from: Role of serotonin in human placental cytotrophoblast differentiation and gene expression

Kliman, Harvey1; Morris, Nolwenn1

Research facility: Yale University
Published Jul 30, 2025 on Dryad. https://doi.org/10.5061/dryad.b8gtht7qb

Data files

Jul 30, 2025 version files 250.22 MB

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is transported into the human placenta through the serotonin transporter (SERT/SLC6A4) on the surface of the syncytiotrophoblast, where it ultimately makes its way to the circulation within the conceptus. During this transit a significant amount of 5-HT becomes concentrated in the cytotrophoblast nucleus. We used immunochemistry, inhibitors of SERT and transglutaminase 2 (TGM2; the enzyme that mediates the covalent linkage of 5-HT to protein glutamine residues—a process known as serotonylation), and RNA sequencing to elucidate the mechanism and consequences of this nuclear localization. Exogenous 5-HT recapitulated the uptake of 5-HT into the trophoblasts and its preferential concentration in cytotrophoblast nuclei we observed in the intact placenta. Inhibiting SERT with escitalopram or TGM2 with cystamine blocked cytotrophoblast differentiation in vitro; namely, flattening, aggregation and forming syncytia. Cystamine eliminated the staining of the nuclei in placental explants by exogenous 5-HT, suggesting that serotonylation mediated this phenomenon. This was confirmed by western blots and immunoprecipitation which identified histone 3 (H3), and specifically the 5th glutamine residue in H3, as a site of serotonylation. Blocking serotonylation led to marked changes in RNA expression. Of the 38,524 mRNAs identified in these trophoblasts, cystamine changed the expression of 1,986 and escitalopram significantly altered 374. Both treatments altered the expression of 155 mRNAs either positively or negatively. In general, the genes that were downregulated were involved with cell proliferation, morphogenesis, motility, and growth—while genes that were upregulated controlled cell survival and protection pathways. These findings suggests that maternal 5-HT promotes placental, embryonic/fetal, and organismal development through histone serotonylation and consequent alterations in gene expression. They raise the possibility that alterations in 5-HT flux in the placenta affect placental and fetal growth, as well as organismal somatic and neurologic developmental trajectories.