Histone monoaminylation dynamics are regulated by a single enzyme and promote neural rhythmicity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE209834 | GEO | 2022/12/06
REPOSITORIES: GEO
Similar Datasets
Project description:Histone monoaminylation is a new class of chromatin post-translational modification whereby glutamines are transamidated by tissue transglutaminase 2 (TGM2). Initial studies of these marks have identified serotonylation and dopaminylation on H3Q5, suggesting the modification is a marker of active chromatin. However, little work has been conducted to understand the regulation of TGM2-mediated monoaminylation of chromatin. Here, we employed a highly sensitive TGM2 assay using the small molecule biotin-cadaverine as an acyl-acceptor substrate. In doing so, we discovered that, in addition to H3Q5, H3Q19 and H2A.ZQ123 and Q124 are glutaminyl substrates for TGM2 in vitro. Modification of these residues occurs in a sequence independent manner, with the primary determining factor for substrate selectivity being steric accessibility. We demonstrated that moving substrate glutamines near the histone fold domain turns them into non-substrates. Furthermore, we found that steric accessibility of glutamines appears to be controlled by higher order chromatin structures. Using nucleosome arrays as substrates, we successfully showed that formation of chromatin fibers in vitro reduces levels of monoaminylation. We then successfully extended these findings to a cell based system, showing that TGM2 is not enriched in heterochromatin and that H3Q5 serotonylation and H3K9me3 are mutually exclusive marks. In total, our results strongly suggest that TGM2, and monoaminylation, are excluded from heterochromatin based on steric accessibility
2022-10-05 | GSE198978 | GEO
Project description:Chemical modifications of histone proteins, along with the ?writers,? ?erasers? and ?readers? of these modifications, are capable of mediating a diverse set of DNA-templated processes including gene transcription1-7. Here, we provide evidence for a new class of histone posttranslational modification (PTM), serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in serotonin (5-hydroxytryptamine, 5-HT) producing organisms. We demonstrate that the tissue Transglutaminase 2 (TGM2) enzyme, a transamidase that is both necessary and sufficient to deposit the mark, can serotonylate H3 on lysine 4 tri-methylated (H3K4me3) nucleosomes resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with predicted enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of its enrichment in human serotonergic neurons, developing mouse brain and cultured serotonergic cells, using an H3K4me3Q5ser specific antibody, indicate that the mark is enriched in euchromatin, is sensitive to cellular differentiation and correlates with permissive gene expression, phenomena that are linked to the mark?s potentiation of TFIID8-10 interactions with H3K4me3. Cells ectopically expressing an H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser target loci leading to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signaling, in the mediation of permissive gene expression in mammalian cells, and further define its biophysical activities as a putative co-regulator of TFIID recruitment to H3K4me3 marked chromatin.
2018-12-18 | GSE106495 | GEO
Project description:Asthma is a heterogeneous disease. Exercise-induced bronchoconstriction (EIB) is a distinct syndrome that occurs in 30-50% of asthmatics and is characterized by high levels of pro-inflammatory eicosanoids. We identified genes differentially expressed in the airways of asthmatics with EIB relative to asthmatics without EIB. Genes related to epithelial repair and mast cell infiltration including beta-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. We confirmed that two novel mediators trefoil factor 3 (TFF3) and transglutaminase 2 (TGM2) have increased expression in airways cells and secreted product in the airways. In vitro studies indicate that 1) TFF3 induces nitric oxide synthase in airway epithelial cells from asthmatics and 2) TGM2 augments the enzymatic activity of secreted phospholipase A2 (sPLA2) group X, an enzyme recently been implicated in asthma pathogenesis. Since PLA2 serves as the first rate-limiting step leading to eicosanoid generation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma. EIB positive and EIB negative subjects sampled pre- and post-exercise
2010-11-10 | E-GEOD-13785 | biostudies-arrayexpress
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:Asthma is a heterogeneous disease. Exercise-induced bronchoconstriction (EIB) is a distinct syndrome that occurs in 30-50% of asthmatics and is characterized by high levels of pro-inflammatory eicosanoids. We identified genes differentially expressed in the airways of asthmatics with EIB relative to asthmatics without EIB. Genes related to epithelial repair and mast cell infiltration including beta-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. We confirmed that two novel mediators trefoil factor 3 (TFF3) and transglutaminase 2 (TGM2) have increased expression in airways cells and secreted product in the airways. In vitro studies indicate that 1) TFF3 induces nitric oxide synthase in airway epithelial cells from asthmatics and 2) TGM2 augments the enzymatic activity of secreted phospholipase A2 (sPLA2) group X, an enzyme recently been implicated in asthma pathogenesis. Since PLA2 serves as the first rate-limiting step leading to eicosanoid generation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma.
2010-11-10 | GSE13785 | GEO
Project description:Dopaminylation of Histone H3 in Ventral Tegmental Area Regulates Cocaine-seeking
| PRJNA510647 | ENA
Project description:Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced maladaptive plasticity
| PRJNA717243 | ENA
Project description:This model is described in the article:
Kinetics of histone gene expression during early development of Xenopus laevis.
Koster JG, Destrée OH and Westerhoff HV. J Theor Biol.
1988 Nov 21;135(2):139-67. PMID: 3267765
Abstract:
Using literature data for transcriptional and translational rate constants, gene copy numbers, DNA concentrations, and stability constants, we have calculated the expected concentrations of histones and histone mRNA during embryogenesis of Xenopus laevis. The results led us to conclude that: (i) for X. laevis the gene copy number of the histone genes is too low to ensure the synthesis of sufficient histones during very early development, inheritance from the oocyte of either histone protein or histone mRNA (but not necessarily both) is necessary; (ii) from the known storage of histones in the oocyte and the rates of histone synthesis determined by Adamson and Woodland (1977), there would be sufficient histones to structure the newly synthesized DNA up to gastrulation but not thereafter (these empirical rates of histone synthesis may be underestimates); (iii) on the other hand, the amount of H3 mRNA recently observed during early embryogenesis (Koster, 1987, Koster et al., 1988) could direct a higher and sufficient synthesis of H3 protein, also after gastrulation. We present a quantitative model that accounts both for the observed H3 mRNA concentration as a function of time during embryogenesis and for the synthesis of sufficient histones to structure the DNA throughout early embryogenesis. The model suggests that X. laevis exhibits a major (i.e. some 14-fold) reduction in transcription of histone genes approximately 11 hours after fertilization. This reduction could be due to a decrease in the number of transcribed histone genes, a decreased rate constant of transcription with continued transcription of all the histone genes, and/or a reduction in the time during the cell cycle in which histone mRNA synthesis takes place. Alternatively, the histone mRNA stability might decrease approximately 16-fold 11 hours after fertilization.
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2005-01-01 | MODEL5954483266 | BioModels
Project description:Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogs of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analog (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homolog, LSD2. LSD1 inhibitor bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460 with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.
2014-11-07 | GSE55089 | GEO