Histone monoaminylation is a novel epigenetic mechanism in psychiatric disorders

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: Feb. 18, 2025

Monoamines, basic nitrogenous molecules containing one amine group, include serotonin, adrenaline, noradrenaline, dopamine, and histamine. They are mainly synthesized due to decarboxylation of amino acids or by transamination amination ketones aldehydes (Al-Kachak Maze, 2023). important neurotransmitters in the body, especially central nervous system, but also peripheral enteric system.Protein monoaminylation is covalent bonding biogenic monoamines glutamine residues some proteins a transamidation reaction. It was first described Heinrich Waelsch's group 1950s (Sarkar et al. 1957;Al-Kachak This showed that mono-and polyamines can be included into livers obtained from guinea pigs, mice, rats, rabbits, with help calcium-dependent transglutaminases (TGMs). In mammals nine isozymes have been delineated (Zhuang Khosla, 2019). Human TGM2 multifunctional ubiquitous takes part many cellular processes such as apoptosis, development, differentiation, wound healing, angiogenesis (Kim Park, 2020). cell located cytosol, nucleus, surface, extracellularly (Keillor al., 2015). has functions depending on its localization allosterically stimulated calcium ions deactivated guanosine triphosphate comprises 687 acid four-domain structure molecular weight about 70 kDa TGMs cross-link γ-carboxamide residue ϵ-amino lysine 2020), catalyse target (Jiang 2012;Al-Kachak Since work including fibronectin, fibrinogen, actin, myosin found monoaminylated (Bader, 2019),Modifications histones well-established epigenetic mechanism regulation gene expression transduce environmental signals modulate (Vanzan 2023;Wu Histones undergo dynamic reversible biochemical posttranslational modifications (Kennelly Histone acetylation deacetylation best studied undergo. Others methylation, phosphorylation, sumoylation, ADP-ribosylation, citrullination, proline isomerisation 2023).Histone reduce positive charges histone tails hence binding affinity negatively charged DNA Additionally, form extra sites for like ATP-dependent chromatinremodelling complexes which contain subunits specifically attach specific modifications. These may enhance accessibility neighbouring sequences modifying removing histones. The chromatin-remodelling synergistically act open up promoters regulatory regions, thereby permitting trans-factors, RNA polymerase II, general transcription factors (GTFs) 2023).A relatively new type modification (Figure 1). shown chicken erythrocytes Ballestar colleagues (1996). 2019, Ian Maze's using sophisticated techniques methodologies induced pluripotent stem cells, preparation truncated recombinant histones, serotonylation happens at position 5 (Q5ser) H3 organisms make serotonin (Farrelly workers tissue nuclesosomes having trimethylated 4 (H3K4me3) leading formation H3K4me3Q5ser. latter molecule shows pattern mammalian tissues, brain gastrointestinal tract, both known large amounts serotonin.Studies across genome human serotonergic neurons, murine developing brain, cultured cells suggest H3K4me3Q5ser nucleosomes increased euchromatin, responsive differentiation associated Maze increases factor IID (TFIID) H3K4me3 augments (Girault, express ectopically mutant cannot serotonylated show markedly changed H3K3me3Q5ser-target loci, deficits Hence, inferred there direct role permissive different neurotransmission signalling.The same undergoes control during placental corresponds changes affect metabolic (Chan 2024). used transgenic mice depends uptake transporter (SERT). SERT deletion decreases enrichment genome, affects neurodevelopmental networks genes early embryonic tissues brain. authors these data placenta interface maternal physiology development foetal 2024).However, more research necessary completely determine how involvement modulates tissue-specific functions. Moreover, full catalogue their downstream effects neurodevelopment could explain unusual monoamine mechanisms risk disorders 2024).Histamine, involved monoaminylation. recently histaminylation catalysed occurs (Q5). H3Q5his antibody they produced validated concentrations synthesis histamine namely, tuberomammillary nucleus (TMN), according sleep-wake patterns. were affected drugs influence sleep "writer" an "eraser" "rewriter" H3. found, based several structural studies, reduces H3K4 methylation mixed lineage leukemia (MLL) complex (a family methyltransferases) (Zheng 2025).Monoaminylation investigated psychiatric disorders. after stress and/or antidepressant exposures. combination genome-wide studies dorsal raphe (DRN) male female subjected chronic social defeat stress, DRN patients major depressive disorder (MDD). effect exposure MDD association between H3K4me3Q5Ser related MDD. stress-induced MDD-linked (fluoxetine) exposures, viral-mediated therapy decrease levels study impact behaviour stress. influences transcriptional plasticity. Chronically-stressed abnormal activity DRN, antidepressant-and disruption this proving adequate behaviour. Corresponding patterns seen on-as compared off-antidepressant time death. antidepressant-associated separate neurotransmission, clinical drug 2024).Maze's discovered 2020 dopamine forms bonds H3Q5dop (Lepack Dopamine learning memory, reward, substance abuse, motor function Lepack (2020) liquid chromatography-mass spectrometry (LC-MS/MS) enzymatic assays serotonylation, dopaminylation catalyzed H3Q5, isolated (H3Q5dop) conjunction K4 trimethylation (H3K4me3Q5dop) correlates ventral tegmental area (VTA), region where behavioural decreased rat well post-mortem following continuous use cocaine. VTA dysregulation timing cocaine intake withdrawal.To better learn functional raised abstinence, delivered dominant viral vectors rats RNA-sequencing virally -affected reduced reverse normally observed withdrawal. addition, decreasing prevented cocaine-seeking -induced release accumbens, reward receives dopaminergic nerve supply VTA. findings suggested roles mediating independent occurrence vulnerability abuse relapse.In addition disorders, noted other cancer (Li Currently most commonly tail 2014), although it possible targeted.Modified pathogenesis (Panariello 2022). However, involve discussed preceding sections above review still very much infancy. evidence suggesting As sections, plays seeking contributes stress-and (fluoxetine)-mediated established modifications, disorders.There difficulties interpretation (Park 2022;Paul Potter, 2024): extreme complexity brain; temporal variations modifications; type; laboratory required; determining whether cause disease process.As mentioned, TGM2. Inhibitors targeting developed, encompassing irreversible types, undergoing trials conditions celiac sprue, neurodegenerative (Song 2017;Badarau 2015;Keillor Johnson, 2021). overall efficacy present psychotropic arguably no than ones introduced fifty years ago, improving outcomes (Paul urgently needed developments current article, is, TGM2, field neuroscience drugs. somewhat speculative, date, even preclinical (phase 0) not conducted area.Moreover, interconnected if abnormalities particular patient, likely (Aljabali 2024), compounding finding effective acting epigenetically treating

Language: Английский

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The Role of Proteomics and Genomics in the Development of Colorectal Cancer Diagnostic Tools and Potential New Treatments

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Language: Английский

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Biomarkers for the detection of circulating tumor cells

Experimental Cell Research, Journal Year: 2025, Volume and Issue: 448(1), P. 114555 - 114555

Published: April 12, 2025

Language: Английский

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pH-Controlled Chemoselective Rapid Azo-Coupling Reaction (CRACR) Enables Global Profiling of Serotonylation Proteome in Cancer Cells

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(10), P. 4457 - 4466

Published: Aug. 29, 2024

Serotonylation has been identified as a novel protein posttranslational modification for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known TGM2 or TGase2) was proven to act main "writer" enzyme this PTM, number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, transporter, histone H3) have characterized substrates serotonylation. However, due lack pan-specific antibodies serotonylated glutamine, precise enrichment proteomic profiling serotonylation still remain challenging. In our previous research, we developed aryldiazonium probe specifically label in bioorthogonal manner, which depended on pH-controlled chemoselective rapid azo-coupling reaction. Here, report application photoactive aryldiazonium-biotin global proteome cancer cells. Thus, over 1,000 were from HCT 116 cells, many are highly related carcinogenesis. Moreover, sites these determined, attributed successful chemical approach. Overall, findings provided new insights into significant association cellular development, further suggesting that target TGM2-mediated monoaminylation may serve promising strategy therapeutics.

Language: Английский

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