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

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.