Methylation Reactions Research Articles

M6A-modified circCacna1c regulates necroptosis and ischemic myocardial injury by inhibiting Hnrnpf entry into the nucleus

BackgroundCircular RNAs (circRNAs) are differentially expressed in various cardiovascular diseases, including myocardial infarction (MI) injury. However, their functional role in necroptosis-induced loss of cardiomyocytes remains unclear. We identified a cardiac necroptosis-associated circRNA transcribed from the Cacna1c gene (circCacna1c) to investigate the involvement of circRNAs in cardiomyocyte necroptosis.MethodsTo investigate the role of circCacna1c during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with hydrogen peroxide (H2O2) to induce reactive oxygen species (ROS)-induced cardiomyocyte death. The N6-methyladenosine (m6A) modification level of circCacna1c was determined by methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP–qPCR) analysis. Additionally, an RNA pull-down assay was performed to identify interacting proteins of circCacna1c in cardiomyocytes, and the regulatory role of circCacna1c in target protein expression was tested using a western blotting assay. Furthermore, the MI mouse model was constructed to analyze the effect of circCacna1c on heart function and cardiomyocyte necroptosis.ResultsThe expression of circCacna1c was found to be reduced in cardiomyocytes exposed to oxidative stress and in mouse hearts injured by MI. Overexpression of circCacna1c inhibited necroptosis of cardiomyocytes induced by hydrogen peroxide and MI injury, resulting in a significant reduction in myocardial infarction size and improved cardiac function. Mechanistically, circCacna1c directly interacts with heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in the cytoplasm, preventing its nuclear translocation and leading to reduced Hnrnpf levels within the nucleus. This subsequently suppresses Hnrnpf-dependent receptor-interacting protein kinase 1 (RIPK1) expression. Furthermore, fat mass and obesity-associated protein (FTO) mediates demethylation of m6A modification on circCacna1c during necrosis and facilitates degradation of circCacna1c.ConclusionOur study demonstrates that circCacna1c can improve cardiac function following MI-induced heart injury by inhibiting the Hnrnpf/RIPK1-mediated cardiomyocyte necroptosis. Therefore, the FTO/circCacna1c/Hnrnpf/RIPK1 axis holds great potential as an effective target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.Graphical

Metabolic regulation of RNA methylation by the m6A-reader IGF2BP3.

The interplay of RNA modifications - deposited by "writers", removed by "erasers" and identified by RNA binding proteins known as "readers" - forms the basis of the epitranscriptomic gene regulation hypothesis. Recent studies have identified the oncofetal RNA-binding protein IGF2BP3 as a "reader" of the N6-methyladenosine (m6A) modification and crucial for regulating gene expression. Yet, how its function as a reader overlaps with its critical oncogenic function in leukemia remains an open question. Here, we report the novel finding that the reader IGF2BP3 reprograms cellular metabolism, resulting in an altered ability of the "writers" to modify the epitranscriptome. In leukemia cells, IGF2BP3 supports increased glycolytic flux and one-carbon metabolism, leading to increased production of S-adenosyl methionine (SAM), a key substrate for methylation reactions within the cell. IGF2BP3 directly regulates the translation of MAT2B, the regulatory subunit of the methionine-adenosyltransferase complex, which is the final enzyme in a pathway leading to SAM production. This, in turn, results in increased m6A modifications on RNA, resulting in positive feedback regulation. This novel mechanism illustrates how metabolism mutually acts with epitranscriptomic modifications, underscoring the pervasive impact of IGF2BP3 in gene regulatory mechanisms governing a broad range of cancer-specific processes.

Examining prestructured β-actin peptides as substrates of histidine methyltransferase SETD3

The Nτ-His73 methylation of β-actin by histidine methyltransferase SETD3 is required for the integrity of the cellular cytoskeleton. Modulation of SETD3 activity in human cells facilitates cancer-like changes to the cell phenotype. SETD3 binds β-actin in an extended conformation, with a conserved bend-like motif surrounding His73. Here, we report on the catalytic specificity of SETD3 towards i, i + 3 stapled β-actin peptides possessing a limited conformational freedom surrounding the His73 substrate residue via positions Glu72 and Ile75. Stapled β-actin peptides were observed to be methylated less efficiently than the linear β-actin peptide. None of the stapled β-actin peptides efficiently inhibited the SETD3-catalyzed Nτ-His73 methylation reaction. Molecular dynamics simulations demonstrated that the unbound and SETD3-bound β-actin peptides display different backbone flexibility and bend-like conformations, highlighting their important role in substrate binding and catalysis. Overall, these findings suggest that reduced backbone flexibility of β-actin prevents the formation of optimal protein-peptide interactions between the enzyme and substrate, highlighting that the backbone flexibility needs to be considered when designing β-actin-based probes and inhibitors of biomedically important SETD3.

Palladium-Catalyzed Cascade Distal C-H Methylation and Cyclization for the Construction of Spirooxindole Skeletons.

Transition metal-catalyzed C-H methylation represents a straightforward approach for introducing methyl groups into organic molecules. Herein, we report a palladium-catalyzed alkene-relayed remote C-H methylation reaction that utilizes dimethyl carbonate as the methylation reagent. The aryl groups distal to a bromo group were dimethylated via C-H activation, leading to the formation of spirooxindoles as the final products through C(sp3)-H activation and C(sp3)-C(sp3) coupling. This cascade process involves the formation of four C-C bonds and the activation of three C-H bonds. The reaction not only provides a new approach to C-H methylation but also offers a novel method for constructing spirooxindole skeletons by merging skeleton construction and methylation into a single step.

Doping In Vivo Alkylation in E. coli by Introducing the Direct Sulfurylation Pathway of S. cerevisiae

AbstractMethylation and alkylation are important techniques used for the synthesis and derivatisation of small molecules and natural products. Application of S‐adenosylmethionine (SAM)‐dependent methyltransferases (MTs) in biotechnological hosts such as Escherichia coli lowers the environmental impact of alkylation compared to chemical synthesis and facilitates regio‐ and chemoselective alkyl chain transfer. Here, we address the limiting factor for SAM synthesis, methionine supply, to accelerate in vivo methylation activity. Introduction of the direct sulfurylation pathway, consisting of O‐acetylhomoserine sulfhydrolase (ScOAHS) and O‐acetyltransferase (ScMET2), from S. cerevisiae into E. coli and supplementation with methanethiol or the corresponding disulfide improves atom‐economic methylation activity in three different MT reactions. Up to 17‐fold increase of conversion compared to the sole expression of the MT and incorporation of up to 79 % of the thiol compound added were achieved. Promiscuity of ScOAHS allowed in vivo production of methionine analogues from organic thiols. Further co‐overproduction of a methionine adenosyltransferase yielded SAM analogues which were further transferred by MTs onto different substrates. For methylation of non‐physiological substrates, conversion rates up to 73 % were achieved, with an isolated yield of 41 % for N‐methyl‐2,5‐aminonitrophenol. The here described technique enables E. coli to become a biotechnological host for improved methylation and selective alkylation reactions.

Doping In Vivo Alkylation in E. coli by Introducing the Direct Sulfurylation Pathway of S. cerevisiae.

Methylation and alkylation are important techniques used for the synthesis and derivatisation of small molecules and natural products. Application of S-adenosylmethionine (SAM)-dependent methyltransferases (MTs) in biotechnological hosts such as Escherichia coli lowers the environmental impact of alkylation compared to chemical synthesis and facilitates regio- and chemoselective alkyl chain transfer. Here, we address the limiting factor for SAM synthesis, methionine supply, to accelerate in vivo methylation activity. Introduction of the direct sulfurylation pathway, consisting of O-acetylhomoserine sulfhydrolase (ScOAHS) and O-acetyltransferase (ScMET2), from S. cerevisiae into E. coli and supplementation with methanethiol or the corresponding disulfide improves atom-economic methylation activity in three different MT reactions. Up to 17-fold increase of conversion compared to the sole expression of the MT and incorporation of up to 79 % of the thiol compound added were achieved. Promiscuity of ScOAHS allowed in vivo production of methionine analogues from organic thiols. Further co-overproduction of a methionine adenosyltransferase yielded SAM analogues which were further transferred by MTs onto different substrates. For methylation of non-physiological substrates, conversion rates up to 73 % were achieved, with an isolated yield of 41 % for N-methyl-2,5-aminonitrophenol. The here described technique enables E. coli to become a biotechnological host for improved methylation and selective alkylation reactions.

Sustainable C-H Methylation Employing Dimethyl Carbonate.

The use of CO2 and CO2-derived chemicals offers society sustainable and biocompatible chemistry for a variety of applications, ranging from materials to medicines. In this context, dimethyl carbonate (DMC) stands out owing to its low toxicity, high biodegradability, tunable reactivity, and sustainable production. Further, the ability of DMC to act as an ambient electrophile at varied temperatures and reaction conditions in order to produce methoxycarbonylated (via BAC2) and methylated products (via BAL2) is very promising. While the methylation of hetero-H (N-, O-, and S-methylation) with DMC is established and well-reviewed, the C-H methylation reaction with DMC is limited, and there is no specific literature detailing the C-methylation reaction using DMC, creating new opportunities as well as challenges in the same domain. In this context, the present perspective focuses on the new breakthroughs, recent advances, and trends in C-H methylation reactions employing DMC. A critical analysis of the mechanistic course of reactions under each category was undertaken. We believe this timely perspective will offer an in-depth analysis of existing literature with critical remarks, which will certainly inspire fellow researchers across disciplines to understand and pursue cutting-edge research in the area of C-H methylation (alkylation) using DMC and related organic carbonates.

Comparative profiling of the absorbed compounds and metabolites, and pharmacokinetic studies of Danshen-Chuanxiong herb pair in rat plasma and brain using liquid chromatography-tandem mass spectrometry

Danshen-Chuanxiong (DS-CX) was a classic herb pair commonly used to treat ischemic stroke. Nevertheless, the metabolic conversion and pharmacokinetic behavior of DS-CX in vivo remains unclear. This work aimed to reveal the in vivo metabolic behavior of DS-CX through establishing metabolic profiles and performing multicomponent pharmacokinetics analysis. The mass defect filtering (MDF) strategy integrated with UHPLC-QTOF-MS was firstly developed to characterize the metabolites of DS-CX in rats’ plasma and brain. Moreover, a sensitive UHPLC-QQQ-MS method was utilized to perform the comparative pharmacokinetic studies of major active ingredients of DS-CX in rats’ plasma. A total of 111 exogenous compounds (29 prototype compounds and 82 metabolites) were identified in rat biological samples. The major metabolic pathways were hydroxylation, methylation, deoxidation, dehydration, hydrogenation, demethylation, hydrolysis, decarboxylation and glucuronidation binding reactions. According to the results of metabolites profiling, sixteen active compounds (8 phenolic acids, 5 phthalides and 3 tanshinones) were selected as markers for further comparative pharmacokinetics study. Compared with the oral administration of DS or CX alone, the higher Cmax of salvianolic acid B, crytotanshinone and tanshinone IIA; the shorter Tmax of lithospermic acid, rosmarinic acid and tanshinone IIA; as well as the higher AUC0−∞ of ferulic acid, rosmarinic acid, salvianolic acid B, senkyunolide I and crytotanshinone, could be found after co-administration of DS-CX (P < 0.05). This study provided the overall knowledge of metabolites profiling of DS-CX in vivo, which would help to understand the effective material basis and promote the clinical application of DC-CX herb pair.

Cofactor binding triggers rapid conformational remodelling of the active site of a methyltransferase ribozyme

The methyltransferase ribozyme SMRZ-1 utilizes S-adenosyl-methionine (SAM) and Cu (II) ions to methylate RNA. Comparison of the SAM bound and unbound RNA structures has shown a conformational change in the RNA. However, the contribution of specific interactions and the role of a pseudo-triplex motif in the catalytic centre on the methylation reaction is not completely understood. In this study, we have used atomic substitutions and mutational analysis to investigate the reaction specificity and the key interactions required for catalysis. Substitution of the fluorescent nucleotide 2-aminopurine within the active ribozyme enabled the conformational dynamics of the RNA upon co-factor binding to be explored using fluorescence spectroscopy. We show that fast co-factor binding (t1/2 ∼ 0.7 seconds) drives a conformational change in the RNA to facilitate methyl group transfer. The importance of stacking interactions at the pseudo-triplex motif and chelation of the Cu (II) ion were shown to be essential for SAM binding.

Study on the metabolism of Xiao-Jian-Zhong-Tang in rats with chronic atrophic gastritis coupled with bioinformatics.

Xiao-Jian-Zhong-Tang (XJZT) has the effect of warming the middle and tonifying the deficiency, easing the urgency and relieving pain according to the theory of traditional Chinese medicine (TCM), and is able to treat spleen deficiency type chronic atrophic gastritis (CAG). Metabolites of TCM in cecum contents are common metabolites of intestinal bacteria and hosts, which can reflect the metabolic status in disease states. The present work was performed to study the effect of XJZT against CAG coupled with the cecal metabolites analysis and bioinformatics. A total of nine prototypical components and 144 metabolites were firstly identified in the cecum metabolites of XJZT using ultra-high performance liquid chromatography added to the quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF/MS), which underwent the metabolism of oxidation, reduction, methylation, and glucuronic acid reaction Furthermore, different prototypical compounds might metabolize into identical metabolites in the presence of intestinal flora. Bioinformatics was further used to correlate these metabolites with the disease and intestinal flora. Components and targets were screened by Cytoscape, and molecular docking of key targets and core components showed good binding ability. This study provided important information for exploring the mechanism of TCM formulae.

Isolation, purification, and structural elucidation of a water-soluble polysaccharide derived from Phellinus baumii Pilát mycelia

This study involved the successful production of mycelial polysaccharides by optimizing submerged culture conditions of Phellinus baumii Pilát. Then, the investigation focused on the composition and chemical structure of the water-soluble polysaccharide from P. baumii Pilát mycelia (PBMP) by extraction and purification. Specifically, this study indicated that a water-soluble PBMP fraction 1 (PBMP1) was isolated from PBMP. Moreover, this study discovered a PBMP1 isolated from PBMP, which was found to have the monosaccharide compositions comprised of fucose (Fuc), glucose (Glc), and galactose (Gal) despite the absence of proteins. Subsequently, the composition and structure of PBMP1 were characterized using Fourier transform infrared (FT-IR) spectroscopy, periodate oxidation, Smith degradation, methylation reaction, gas chromatography-mass spectrometer (GC-MS), and Nuclear magnetic resonance (NMR). The composition and structure of PBMP1 were characterized in this study, revealing an α-glycosidic bond conformational linkage with 1,4-Glc residues and 1,6-Gal residues forming the backbone. Additionally, a highly branched hetero-polysaccharide was identified with a non-reducing terminus of Fuc containing 1,3,4- and 1,4,6-Glc branching. The findings of this study offer valuable insights and information that can be utilized by researchers, manufacturers, and other stakeholders to advance the field of P. baumii Pilát product development. Moreover, these results have significant implications for future large-scale mass production and functional applications of PBMP1 products.

Antimicrobial and Molecular Docking Studies of 1,3,4-Thiadiazole Tethered Sulfa-Azo Derivatives via Hydrazono-Methyl Bridge

A new series of 1,3,4-thiadiazole linked to sulfa-azo derivatives via hydrazono-methyl bridge were synthesized via the reaction of methyl ((E)-(sulfa-derivatives)diazenyl) benzylidene)hydrazine-1-carbodithioates 1a-e with ethyl ester and acetyl hydrazonyl halides 2a-d. The chemical structures of the newly 1,3,4-thiadiazoles 3a-t have been clarified considring their elemental and spectral analysis. Antimicrobial activity of the newly 1,3,4-thiadiazoles was determined for Staphylococcus aureus, Escherichia coli, Candida albicans, as well as Aspergillus niger using the cup agar plate diffusion method. Out of the twenty compounds, compounds 3j, 3k, 3l, and 3s with isoxazole sulfonamides were selected for MIC assay. Compound 3j was equipotent with neomycin control drug against all tested strains, while compound 3k was 4-fold higher than neomycin against S. aureus, E. coli, and C. albicans with MIC values of 9.77, 19.53, and 19.53 μg/mL, respectively. Compound 3l was equipotent with neomycin against S. aureus and C. albicans, while it was 2-fold higher than neomycin against E. coli with MIC of 39.06 μg/mL. For 3s, it was less potent than neomycin against all tested microbs with 2-fold and 4-fold less potent. Further scanning electron microscopy (SEM) investigation has been studied to reveal the disruption effect of the selected potent antimicrobial compound (3k) on the intact cells of tested microbs S. aureus, E. coli in addition to C. albicans. Results showed that 3k exhibited a noticeable effect on destroying microbial cell walls. Furthermore, molecular docking study has been done to assess the binding behavior of two most effective compounds 3k and 3l with the target crystal structure of dihydropteroate synthase (PDB: 6CLV for S. aureus) and (PDB: 5U14 for E. coli). Compound 3k was shown to be able to form stable complexes with both target enzymes of dihydropteroate synthase through hydrogen bonding and hydrophobic interactions.

Co-pyrolysis of wheat straw with polyester-based polyurethane for nitrogenous compounds: Pyrolysis kinetic properties and synergistic effects

To re-utilize agricultural waste straw and waste plastic, the co-pyrolysis process of wheat straw (WS) and high-nitrogen polymer polyester-based polyurethane (PU) and the synergistic effects were studied. The results showed that PU facilitated pyrolysis to occur at lower temperatures. The effective apparent activation energies (Eα) of different samples were calculated at different conversion rates with three methods (Kissinger, KAS and Starink). It was found that PU decreased the Eα values and enthalpy change of WS and increased the reactivity. Both ΔG and ΔS results indicate that a heating rate of 5 ℃/min is more favorable for co-pyrolysis. PU greatly promoted the production of pyrolysis oil. Co-pyrolysis oil doped with 75 % PU gave the highest yield of 77 wt%. Co-pyrolysis effectively suppressed the production of acids, aldehydes, and phenols in pyrolysis oils. It increased the levels of alcohols and ketones, improving the pyrolysis oil's stability and calorific value. α, β-unsaturated aldehydes produced by WS during pyrolysis reacted with hydrazine derivatives produced by PU pyrolysis to produce pyrazole compounds after dehydration. In the co-pyrolysis of 50 % doped PU, the reaction of methyl and methylene produced by WS with amines (-NH2) produced by the pyrolysis of PU promotes the production of trimethylamine. The yield of amines in the nitrogenous compounds reached a maximum at this time. PU increased the yield of nitrogenous compounds and their variety. It favored the output of high-value chemicals. FT-IR analyses of pyrolytic charcoal showed that the addition of PU promoted the cleavage of WS and the dehydration and decarboxylation reactions of C-O and C-O-C. Finally, synergistic effects and nitrogen conversion mechanisms in the co-pyrolysis process are proposed. This work provided a theoretical basis for the resource utilization of WS waste and PU waste.

Extra-Annulated Chlorophyll Derivatives by Scholl Reaction.

The ferric chloride assisted Scholl reaction of methyl (3,5-dimethoxyphenyl)carbonyl-pyropheophorbide-a produced an extra-annulated, didehydrogenated chlorophyll derivative with a six-membered ring fused at the pyrrole A-ring. The steric interaction of the substituents on the additional tetralone and B-rings induced molecular helicity. The helically cyclized stereoisomers were separated by recrystallization, and their (P/M)-stereochemistry was confirmed by circular dichroism spectra. The distortion of their chlorin π-systems broadened electronic absorption bands to cover all visible regions and reach the near-infrared region.

Synthesis of Methyl 2-[Bis(benzylthio)phosphoryl]acetate as a Novel Horner–Wadsworth–Emmons-Type Reagent and Its Application to the Diastereodivergent Synthesis of (E)- and (Z)-α,β-Unsaturated Esters

AbstractMethyl 2-[bis(benzylthio)phosphoryl]acetate has proven to be an efficient Horner–Wadsworth–Emmons (HWE)-type reagent for the diastereodivergent synthesis of (E)- and (Z)-α,β-unsaturated esters. Under the conditions of excess NaHMDS relative to the HWE-type reagent, the HWE-type reactions of methyl 2-[bis(benzylthio)phosphoryl]acetate with various aldehydes afforded the corresponding α,β-unsaturated esters in an E-selective manner in up to 100:0 E/Z ratio. However, when an excess of the HWE-type reagent was used relative to NaHMDS, the stereoselectivity of the HWE-type reactions was dramatically changed from E to Z, yielding an E/Z ratio of up to 2:98.

Adsorption efficiency and in-situ catalytic thermal degradation behaviour of microplastics from water over Fe-modified lignin-based magnetic biochar

The efficient removal and degradation of microplastics are critical for protecting aquatic ecosystems. Herein, Fe-modified magnetic biochar (MBC) was synthesized as an adsorbent for removing microplastics in water. The effects of lignin/Fe salt mass ratios, adsorbent amount, adsorption time, adsorption temperature, solution pH, and presence of coexisting anions on adsorption efficiency were investigated. The thermal degradation behaviour and recycling characteristic of microplastics was also explored. Results showed that MBC has a developed pore structure, superparamagnetic property, and abundant oxygen-containing functional groups. The removal efficiency of polystyrene microplastics using MBC-11 was 99 %, with an adsorption capacity of 68.57 mg/g, which was 25 times higher than that of unmodified lignin biochar. The kinetics of the adsorption process followed the pseudo-first kinetic model, and the equilibrium data best fitted the Freundlich model. Thermodynamic results confirmed that adsorption over MBC was a spontaneous, heat-absorbing, and entropy-increasing process. The adsorption mechanism of PS by biochar was mainly via electrostatic and hydrophobic interactions and pore throttle. The thermal-degradation products of PS were mainly hydrocarbons, including styrene, benzene, and toluene, owing to the enhanced β-scission, H-shift, and methylation reactions at MBC catalytic sites. This study provides a scientific basis for the development of control technologies for microplastics removal in water.

Electrocatalytic methylation and amination reactions with CO2 and NOxy–

Electrocatalytic methylation and amination reactions with CO2 and NOxy–

Spectral Assignment in the [3 + 2] Cycloadditions of Methyl (2E)-3-(Acridin-4-yl)-prop-2-enoate and 4-[(E)-2-Phenylethenyl]acridin with Unstable Nitrile N-Oxides

The investigation of cycloaddition reactions involving acridine-based dipolarophiles revealed distinct regioselectivity patterns influenced mainly by the electronic factor. Specifically, the reactions of methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate and 4-[(1E)-2-phenylethenyl]acridine with unstable benzonitrile N-oxides were studied. For methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate, the formation of two regioisomers favoured the 5-(acridin-4-yl)-4,5-dihydro-1,2-oxazole-4-carboxylates, with remarkable exclusivity in the case of 4-methoxybenzonitrile oxide. Conversely, 4-[(1E)-2-phenylethenyl]acridine displayed reversed regioselectivity, favouring products 4-[3-(substituted phenyl)-5-phenyl-4,5-dihydro-1,2-oxazol-4-yl]acridine. Subsequent hydrolysis of isolated methyl 5-(acridin-4-yl)-3-phenyl-4,5-dihydro-1,2-oxazole-4-carboxylates resulted in the production of carboxylic acids, with nearly complete conversion. During NMR measurements of carboxylic acids in CDCl3, decarboxylation was observed, indicating the formation of a new prochiral carbon centre C-4, further confirmed by a noticeable colour change. Overall, this investigation provides valuable insights into regioselectivity in cycloaddition reactions and subsequent transformations, suggesting potential applications across diverse scientific domains.

Mitochondrial One-Carbon Metabolism and Alzheimer's Disease.

Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer's disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer's disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer's disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer's disease pathology.

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis.

The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.