Serotonin through serotonylation impact on gene expresion on human purified trophoblast after 48h in culture
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PROVIDER: PRJNA1277784 | ENA |
REPOSITORIES: ENA
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Project description:Serotonin (5-hydroxytryptamine) plays a critical role in human development in utero. Recent evidence suggests that it is taken up from the maternal circulation and gets concentrated in trophoblasts (Kliman et al., 2018). A novel mechanism involving serotonin has been described: serotonylation, a covalent linkage of 5-HT with protein glutamines mediated by a tissue transglutaminase (Farelly et al., 2019). Our objective was to understand the role of serotonin, through serotonylation, in protein, gene and phenotype expression in human placenta. Trophoblast puriScation and culture, western blot (WB), immunochemistry (IHC), and RNAseq (with IPA) were performed. Experiments were repeated at least 3 times, and corresponding statistical analysis was done. Through WB and IHC, we found that serotonylation seems to be present in human placenta and cytotrophoblasts. Moreover, through IHC and RNAseq/IPA, serotonylation seems to have consequences on gene and phenotype expression; especially on fusion, proliferation and invasion, which leads to implantation and placental structure, initial steps of pregnancy. Through IPA analysis, those phenotype and serotonylation impacted-genes were also found to be involved in embryonic, organismal, tissue and organ development, and especially the brain and behavior, foreshadowing central role in human body physiological development. Lastly, IPA results also showed that those same genes were also involved in many different pathologies, especially ones like Alzheimer, Parkinson, ALS, depression, ASD or cancer (EMT). To conclude, these Sndings seem to show that the human placenta, through the cytotrophoblast, is an essential organ to understand the origin of human life and pathophysiological development. Serotonin, through serotonylation, seems to be central by regulating original embryonic genes involved in different processes during life, especially in initiation of pregnancy (invasion and placentation), development of the human body, behavior, and different pathologies, leading to potential diagnostic or therapeutic options for patients.
2025-06-30 | GSE299974 | GEO
Project description:Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (Sert/Slc6a4). Sert deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in offspring brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.
2024-01-23 | GSE246539 | GEO
Project description:Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (Sert/Slc6a4). Sert deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in offspring brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.
2024-01-23 | GSE246538 | GEO
Project description:Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NEPC tumors produce and accumulate serotonin (5-HT), a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic 5-HT axis as a key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4, independent of serotonin receptor activity. Mechanistically, high level of intracellular 5-HT promotes neuroendocrine differentiation and suppresses androgen receptor (AR) signaling through histone serotonylation at H3K4me3Q5. This epigenetic modification reconfigures the H3K4me3 chromatin landscape and sustains NEPC-specific transcriptional programs. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.
2025-12-16 | GSE295408 | GEO
Project description:<p>Neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has emerged to play parallel roles in both neurobiology and oncology. Apart from receptor-mediated signaling transduction pattern, serotonin can be covalently integrated into histone (the post-translational modification known as histone serotonylation) and serve as an epigenetic mark associated with permissive gene expression. However, how histone serotonylation influences tumorigenesis is yet to be understood. In this study, we observe the higher levels of histone serotonylation (H3K4me3Q5ser) and transglutaminases 2 (TGM2, the enzyme catalyzing serotonylation) in both pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines in comparison with their normal counterparts, and inhibition of histone serotonylation suppresses PDAC development. Mechanistically, we demonstrate that TGM2-mediated histone serotonylation at promoter of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC development by lipid metabolism remodeling. Collectively, this study reveals histone serotonylation as an important driver of PDAC tumorigenesis.Neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has emerged to play parallel roles in both neurobiology and oncology. Apart from receptor-mediated signaling transduction pattern, serotonin can be covalently integrated into histone (the post-translational modification known as histone serotonylation) and serve as an epigenetic mark associated with permissive gene expression. However, how histone serotonylation influences tumorigenesis is yet to be understood. In this study, we observe the higher levels of histone serotonylation (H3K4me3Q5ser) and transglutaminases 2 (TGM2, the enzyme catalyzing serotonylation) in both pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines in comparison with their normal counterparts, and inhibition of histone serotonylation suppresses PDAC development. Mechanistically, we demonstrate that TGM2-mediated histone serotonylation at promoter of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC development by lipid metabolism remodeling. Collectively, this study reveals histone serotonylation as an important driver of PDAC tumorigenesis.</p>
2025-06-13 | MTBLS12569 | MetaboLights
Project description:Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome
| PRJNA1033596 | ENA
Project description:Targeting serotonin-driven histone serotonylation suppresses lineage plasticity and progression of NEPC
| PRJNA1254615 | ENA
Project description:Collective cell migration (CCM) is pivotal in several biological contexts, and posttranslational modifications of histones are essential for initiating this process. Here, we provide evidence for the involvement of a recently discovered chromatin marker, termed histone serotonylation, in the collective migration of cranial neural crest cells—an embryonic multipotent stem cell population. Our in vivo data revealed that histone serotonylation occurs in neural crest cells just before they start migrating and that its occurrence is essential for initiating the collective migration of these cells. Surprisingly, we found that stiffening of the neural crest migratory substrate, the mesoderm, induces histone serotonylation by promoting the nuclear translocation of transglutaminase 2 (Tgm2), an enzyme that catalyzes the addition of serotonin to histones. Moreover, mechanical and molecular perturbations establish that shuttling of Tgm2 into the nucleus and concomitant increases in histone serotonylation are essential to trigger CCM in vivo. Furthermore, a combination of sequencing analyses revealed that histone serotonylation modifies the chromatin landscape to favor gene transcription, supporting the switch from non-migratory to migratory cell states.
2026-09-21 | GSE306655 | GEO
Project description:Collective cell migration (CCM) is pivotal in several biological contexts, and posttranslational modifications of histones are essential to initiate this process. Here, we provide evidence for the involvement of a recently discovered chromatin mark, termed histone serotonylation, in the collective migration of cranial neural crest cells – an embryonic multipotent stem cell population. Our in vivo data reveal that histone serotonylation appears in neural crest cells just before they start migrating and that its occurrence is essential to initiate the collective migration of these cells. Surprisingly, we found that stiffening of the neural crest migratory substrate, the mesoderm, induces histone serotonylation by promoting nuclear translocation of transglutaminase 2 (Tgm2), an enzyme that catalyzes the addition of serotonin to histones . Moreover, mechanical and molecular perturbations establish that mechanical shuttling of Tgm2 into the nucleus, with concomitant increases in histone serotonylation, are both required and sufficient to trigger CCM in vivo. Furthermore, chromatin immunoprecipitation and RNA sequencing analyses uncover a transcriptional module, which is controlled by histone serotonylation in response to mesoderm stiffening. Altogether, our results provide in vivo evidence showing that tissue stiffening serves as an “epigenetic signal” that modifies the chromatin landscape to modulate gene transcription, triggering the switch from non-migratory to migratory cell states.
2026-09-21 | GSE285358 | GEO
Project description:Collective cell migration (CCM) is pivotal in several biological contexts, and posttranslational modifications of histones are essential to initiate this process. Here, we provide evidence for the involvement of a recently discovered chromatin mark, termed histone serotonylation, in the collective migration of cranial neural crest cells – an embryonic multipotent stem cell population. Our in vivo data reveal that histone serotonylation appears in neural crest cells just before they start migrating and that its occurrence is essential to initiate the collective migration of these cells. Surprisingly, we found that stiffening of the neural crest migratory substrate, the mesoderm, induces histone serotonylation by promoting nuclear translocation of transglutaminase 2 (Tgm2), an enzyme that catalyzes the addition of serotonin to histones . Moreover, mechanical and molecular perturbations establish that mechanical shuttling of Tgm2 into the nucleus, with concomitant increases in histone serotonylation, are both required and sufficient to trigger CCM in vivo. Furthermore, chromatin immunoprecipitation and RNA sequencing analyses uncover a transcriptional module, which is controlled by histone serotonylation in response to mesoderm stiffening. Altogether, our results provide in vivo evidence showing that tissue stiffening serves as an “epigenetic signal” that modifies the chromatin landscape to modulate gene transcription, triggering the switch from non-migratory to migratory cell states.
2026-09-21 | GSE285357 | GEO