Serotonin Shapes Placental Gene Expression via Histone Modifications
Publication Title: Role of Serotonin on Gene Expression and Physiology in Human Cytotrophoblasts and Placenta
Summary
- Question
- This study investigated how serotonin (5-hydroxytryptamine or 5-HT) impacts gene expression and cellular processes in the human placenta, specifically in cytotrophoblasts (cells in the placenta that play a role in nutrient exchange and development). The researchers aimed to understand how serotonin's transport and nuclear localization influence cellular differentiation and gene regulation.
- Why it Matters
- Serotonin is commonly recognized as a brain neurotransmitter, but it also plays a critical role in early development, including placental and fetal growth. Disruptions in serotonin's function could have far-reaching implications, including impacts on fetal growth, brain development, and risks for conditions like autism spectrum disorders. Understanding serotonin's role in the placenta may also clarify the effects of medications like selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy.
- Methods
- The researchers used human placental samples and cultured cytotrophoblast cells to study serotonin uptake and localization. Techniques included RNA sequencing (to analyze gene expression), immunohistochemistry (to visualize serotonin and related proteins), and treatments with specific inhibitors such as escitalopram (an SSRI) and cystamine (an inhibitor of protein serotonylation, which is the attachment of serotonin to proteins).
- Key Findings
- Serotonin was transported into cytotrophoblast cells via the serotonin transporter (SERT) and concentrated in the nucleus. This nuclear localization was mediated by serotonylation, a chemical modification involving serotonin. Blocking SERT with escitalopram or inhibiting serotonylation with cystamine disrupted cytotrophoblast differentiation and altered the expression of hundreds of genes. Upregulated genes were associated with cell survival, while downregulated genes were linked to cell growth and development. These findings suggest that serotonin promotes placental and fetal development through its effects on gene expression.
- Implications
- This research highlights serotonin's essential role in placental development, with potential downstream effects on fetal growth and brain development. It suggests that disruptions in serotonin transport or serotonylation, such as those caused by SSRIs, could influence pregnancy outcomes and child development. The findings may help explain observed links between SSRI use during pregnancy and lower birth weights or increased autism risk.
- Next Steps
- Future research should identify other nuclear proteins affected by serotonylation and explore how serotonin impacts broader placental and fetal processes. Additional studies could also investigate how altered serotonin pathways contribute to developmental conditions, such as autism, and evaluate potential interventions to mitigate these effects.
- Funding Information
- This research was supported by the Fulbright-Monahan Foundation, the Université de Paris Cité, and the Reproductive and Placental Research Unit at Yale University School of Medicine. The National Institutes of Health also provided support through the Yale Center for Genomic Analysis under Award Number 1S10OD030363-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Full Citation
Morris N, Guller S, Tang Z, Zhang Y, Siegman E, Milano K, Rudnick G, Kliman H. Role of Serotonin on Gene Expression and Physiology in Human Cytotrophoblasts and Placenta. Endocrinology 2025, 166: bqaf124. PMID: 40898405, PMCID: PMC12399332, DOI: 10.1210/endocr/bqaf124.
This AI-assisted summary has been reviewed and approved by at least one of the study's authors to ensure it accurately reflects the research.
Authors
Nolwenn S Morris
First AuthorHarvey Kliman, MD, PhD
Last AuthorResearch Scientist in Obstetrics, Gynecology, and Reproductive Sciences
Additional Yale School of Medicine Authors
Other Authors
Research Themes
Keywords
Concepts
- exogenous 5-HT;
- cytotrophoblast nuclei;
- uptake of 5-HT;
- histone 3;
- differentiation in vitro;
- maternal 5-HT;
- transglutaminase 2;
- fetal growth;
- intact placenta;
- placental explants;
- human cytotrophoblasts;
- gene expression;
- serotonin transporter;
- human placenta;
- placenta;
- serotonin;
- RNA expression;
- Western blotting;
- cell survival;
- cell proliferation;
- escitalopram;
- trophoblast;
- protective pathways;
- SERT;
- serotonylation