Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders DOI Creative Commons
Benjamin H. Weekley,

Newaz I. Ahmed,

Ian Maze

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112092 - 112092

Published: Feb. 22, 2025

The evolving field of neuroepigenetics provides important insights into the molecular foundations brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping epigenetic landscape during neurodevelopment disease. Traditional methods to investigate consequences chromatin-related provide valuable phenotypic but often lack information on biochemical mechanisms underlying these processes. Recent studies, however, are beginning elucidate how structural and/or functional aspects histone, DNA, RNA post-translational modifications affect transcriptional landscapes neurological phenotypes. Here, we review identification regulators from genomic studies disease, as well mechanistic findings that reveal intricacies neuronal chromatin regulation. We then discuss serve a guideline for future investigations. end by proposing roadmap therapies exploit coupling them recent advances targeted therapeutics.

Language: Английский

Circadian rhythms are set by epigenetic marks in neurons DOI
Debosmita Sardar, Tatiana G. Kutateladze

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

Citations

0

Phenethylaminylation: Preliminary In Vitro Evidence for the Covalent Transamidation of Psychedelic Phenethylamines to Glial Proteins using 3,5-Dimethoxy-4-(2-Propynyloxy)-Phenethylamine as a Model Compound DOI Creative Commons
Rajiv Rangan, Russell Petty, Suchismita Acharya

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Abstract Psychedelics are well known for their ability to produce profoundly altered states of consciousness. But, more importantly, the effects psychedelics can influence neurobehavioral changes that last after these acute subjective end. This phenomenon is currently being leveraged in development psychedelic-assisted psychotherapies treatment multiple neuropsychiatric disorders. The cellular and molecular mechanisms by which single doses able mediate long-term cognitive an active area research. We hypothesize contribute long term state covalently modifying proteins. post-translational modification possible through transglutaminase-mediated transamidation amine termini glutamine carboxamide residues. Here, we synthesize utilize a propargylated analogue mescaline – classic serotonergic psychedelic phenethylamine found cacti species identify putative protein targets modifications use click-chemistry primary human astrocyte cell culture model. Our preliminary findings indicate diverse array glial proteins may be substrates transglutaminase 2-mediated monoaminylation our model (“phenethylaminylation”). Based on points, speculatively highlight new directions study this noncanonical activity.

Language: Английский

Citations

0

Histone monoaminylation is a novel epigenetic mechanism in psychiatric disorders DOI Creative Commons
Jacob Peedicayil,

Samuel Santhosh

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

Citations

0

Elucidating neuroepigenetic mechanisms to inform targeted therapeutics for brain disorders DOI Creative Commons
Benjamin H. Weekley,

Newaz I. Ahmed,

Ian Maze

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112092 - 112092

Published: Feb. 22, 2025

The evolving field of neuroepigenetics provides important insights into the molecular foundations brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping epigenetic landscape during neurodevelopment disease. Traditional methods to investigate consequences chromatin-related provide valuable phenotypic but often lack information on biochemical mechanisms underlying these processes. Recent studies, however, are beginning elucidate how structural and/or functional aspects histone, DNA, RNA post-translational modifications affect transcriptional landscapes neurological phenotypes. Here, we review identification regulators from genomic studies disease, as well mechanistic findings that reveal intricacies neuronal chromatin regulation. We then discuss serve a guideline for future investigations. end by proposing roadmap therapies exploit coupling them recent advances targeted therapeutics.

Language: Английский

Citations

0