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 | GSE246538 | 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:Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome
| PRJNA1033596 | ENA
Project description:Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome [RNA-seq]
| PRJNA1033602 | ENA
Project description:Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome [ChIP-seq]
| PRJNA1033600 | ENA
Project description:Serotonylation has been identified as a novel protein post-translational modification (PTM) for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main “writer” enzyme for this PTM and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibody for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to label protein serotonylation in a bioorthogonal manner. This chemical biology tool can be utilized alternatively for the antibody-free enrichment of serotonylated proteins, which depends on a pH-controlled chemoselective rapid azo-coupling reaction (CRACR). Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 500 serotonylated proteins were identified from HCT 116 cells. Importantly, a number of modification sites of these serotonylated proteins were determine, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics.
| PXD054426 |
Project description:The dual challenges of limited therapeutic options caused by de novo or acquired resistance and psychological distress in melanoma patients necessitate innovative treatment strategies. In this study, we identify Paroxetine Hydrochloride (PH), an FDA-approved antidepressant, as a novel therapeutic agent for BRAFV600E-mutated melanoma, including BRAFi/MEKi-resistant cases. Furthermore, our findings unraveled that PH acts as an unrecognized pyroptosis inducer. By triggering pyroptosis, PH remodels the tumor microenvironment to synergize with anti-PD-1 therapy while maintaining a favorable safety profile. Mechanistically, PH impedes serotonin reuptake, leading to epigenetic reprogramming through reduced histone serotonylation at the promoters of DNA repair genes. The impairment of DNA damage repair pathways in turn triggers genomic instability, proteostasis imbalance, and endoplasmic reticulum stress, ultimately inducing pyroptosis. Our findings uncover the underlying mechanism by which 5-HT drives melanoma progression and highlight PH as a promising candidate with multiple clinical potentials for melanoma treatment.
2025-11-20 | GSE282621 | GEO
Project description:The dual challenges of limited therapeutic options caused by de novo or acquired resistance and psychological distress in melanoma patients necessitate innovative treatment strategies. In this study, we identify Paroxetine Hydrochloride (PH), an FDA-approved antidepressant, as a novel therapeutic agent for BRAFV600E-mutated melanoma, including BRAFi/MEKi-resistant cases. Furthermore, our findings unraveled that PH acts as an unrecognized pyroptosis inducer. By triggering pyroptosis, PH remodels the tumor microenvironment to synergize with anti-PD-1 therapy while maintaining a favorable safety profile. Mechanistically, PH impedes serotonin reuptake, leading to epigenetic reprogramming through reduced histone serotonylation at the promoters of DNA repair genes. The impairment of DNA damage repair pathways in turn triggers genomic instability, proteostasis imbalance, and endoplasmic reticulum stress, ultimately inducing pyroptosis. Our findings uncover the underlying mechanism by which 5-HT drives melanoma progression and highlight PH as a promising candidate with multiple clinical potentials for melanoma treatment.
2025-11-20 | GSE282619 | GEO
Project description:we provide evidence for a new class of histone posttranslational modification (PTM): serotonylation.
2018-12-19 | PXD008106 | Pride