key: cord-0725601-ts2808rs authors: Costa dos Santos, Gilson; Renovato-Martins, Mariana; de Brito, Natália Mesquita title: The remodel of the “central dogma”: a metabolomics interaction perspective date: 2021-05-09 journal: Metabolomics DOI: 10.1007/s11306-021-01800-8 sha: b0495e4b7aa7dc70b0d4e63fdde14d579ded94ef doc_id: 725601 cord_uid: ts2808rs BACKGROUND: In 1957, Francis Crick drew a linear diagram on a blackboard. This diagram is often called the “central dogma.” Subsequently, the relationships between different steps of the “central dogma” have been shown to be considerably complex, mostly because of the emerging world of small molecules. It is noteworthy that metabolites can be generated from the diet through gut microbiome metabolism, serve as substrates for epigenetic modifications, destabilize DNA quadruplexes, and follow Lamarckian inheritance. Small molecules were once considered the missing link in the “central dogma”; however, recently they have acquired a central role, and their general perception as downstream products has become reductionist. Metabolomics is a large-scale analysis of metabolites, and this emerging field has been shown to be the closest omics associated with the phenotype and concomitantly, the basis for all omics. AIM OF REVIEW: Herein, we propose a broad updated perspective for the flux of information diagram centered in metabolomics, including the influence of other factors, such as epigenomics, diet, nutrition, and the gut- microbiome. KEY SCIENTIFIC CONCEPTS OF REVIEW: Metabolites are the beginning and the end of the flux of information. Sixty-three years ago, Francis Crick gave a lecture in which he presented the diagram called the "central dogma." This dogma states that the transfer of information from DNA to DNA/RNA, or from nucleic acid to protein, may be possible, but the transfer from protein to protein or protein to nucleic acid is impossible (Cobb, 2017; CRICK, 1957) . The flux of information attained another dimension when small molecules advanced to the forefront of chemical biology. In 2005, Dr. Schreiber was the first to describe small molecules as the missing link in the central dogma and as the central elements of life (Schreiber, 2005) . Consequently, the perception of small molecules as only downstream products became reductionist, as they have been shown to modulate all steps in the flux of information, including the phenotype (Chang et al., 2008; Guijas et al., 2018; Kondratov et al., 2001; Mathew & Padmanaban, 2013; Patti et al., 2012; Rabinowitz & Silhavy, 2013; Yugi & Kuroda, 2018) . In 2016, for the first time, a white paper provided recommendations to include metabolomics in precision medicine (Beger et al., 2016) . In recent years, several papers have described an integrative data analysis with metabolomics (Ahmed et al., 2021; Damiani et al. 2020; Hou et al., 2020; Long et al., 2020; Mussap et al., 2021; Xie et al., 2021) . In the last 20 years, the advance of important analytical tools, such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), has led to the advocacy of small molecules, by the large-scale analysis called metabolomics. These exceptional omics techniques have made it possible to build the Human Metabolome Database (Wishart et al., 2018) and the Biological Magnetic Resonance Data Bank (Ulrich et al., 2007) . The assignment of several metabolites has been extremely important for revealing distinct metabolic pathway shifts related to the phenotype, such as the polyol pathway detour under vitamin D intake , enhanced lipid metabolism in oral cancer (Sant'Anna-Silva, 2018) , glycerol metabolism in osteoarthritis (de Sousa et al., 2017a (de Sousa et al., , 2017b (de Sousa et al., , 2019 , glutaminolysis in cancer (DeBerardinis et al., 2007; Koczula et al., 2016; Rodrigues et al., 2016; Yang et al., 2016) , tumor microenvironments (Costa Dos Santos et al., 2021) , and COVID-19 (Costa dos Santos Junior et al., 2020) . Metabolites are the substrates and products of molecular mechanisms linked to the steps in the flux of information. Molecular modulation can start outside the host organism, as metabolites can come from the metabolism of microorganisms, diet, and other exogenous sources (Johnson et al., 2012; Martin et al., 2007; Tang et al., 2015) . One good example of a metabolite is trimethylamine N-oxide (TMAO), commonly found in urine; it can be generated directly from the diet by ingestion of fish, or indirectly from gut-microbiome choline metabolism (Thøgersen et al., 2020; Thomas & Fernandez, 2021; Ufnal et al., 2015) . TMAO can affect the proteome, as MAP kinase and nuclear factor-κB (NF-κB) proteins can be activated by TMAO in endothelial cells, and high levels of this metabolite are associated with cardiovascular diseases (Bennett et al., 2013; Gibson et al., 2020; Seldin et al., 2016; Zeisel & Warrier, 2017) . The mechanism of interaction of TMAO with proteins is still unknown; however, there is evidence that it can influence enzyme activity and protein stability (Hu et al., 2010; Mashino & Fridovich, 1987) . TMAO can affect the genome, epigenome, and transcriptome by stabilizing DNA G-quadruplex structures (Knop et al., 2018; Ueda et al., 2016) , altering levels of DNA methylation (Knight et al., 2018) , and stabilizing RNA tertiary structures (Denning et al., 2013; Lambert et al., 2010) , respectively. In addition, other factors can affect TMAO levels, such as age and sex (Rossner et al., 2017) . Herein, we discuss various pieces of evidence to shed light on the main role of metabolites shaping the other omics levels, such as the epigenome, genome, transcriptome, and proteome (Adamski & Suhre, 2013; Anders et al., 2014; Bhaduri et al., 2018; Choi et al., 2018; Dervan, 2001; Etchegaray & Mostoslavsky, 2016; Francisco & Paulo, 2018; Gao et al., 2016; Kimball & Vondriska, 2020; Neidle, 2001; Padmanabhan et al., 2013; Pogribny et al., 2008; Reid et al., 2017; Rodriguez & Miller, 2014; Tzika et al., 2018; Usanov et al., 2018; Wilson & Li, 2012) , as shown in Fig. 1 . In addition, this evidence is particularly important in the multiomics era, because it can reveal the modes of action of small molecules, accelerate drug development (Patel-Murray et al., 2020) , reveal gut-microbiome alterations (Li et al., 2020a (Li et al., , 2020b , and link with machine learning for diagnoses, such as COVID-19 (Delafiori et al., 2021) . Metabolites can interact with macromolecules through competitive and allosteric binding to the active site of enzymes, leading to alterations in enzyme activity. This is not exclusive to enzymes; it occurs in other signaling proteins, such as G protein-coupled receptors (GPCRs). The succinate receptor (SUCNR1/GPR91), a cell-surface sensor for extracellular succinate, was shown to be upregulated in mice-activated macrophages, which function as an autocrine and paracrine sensor for extracellular succinate to enhance interleukin 1β (IL-1β) production (Littlewood-Evans et al., 2016) . The GPCR (GPR132), which can sense and respond to lactate, was shown to promote an M2-like protumoral phenotype in mice macrophages, stimulating cancer metastasis (Chen et al., 2017) . Lactate controls muscle regeneration The small molecules drive all other omics, as a rotor drives the blades in the turbine of a windmill. External factors such as diet, lifestyle, gut-microbiome, age, drug, and sex will affect the metabolomics, e.g. the center of the flux of the information, and consequently affect all other omics by inducing M2-like macrophage polarization (Zhang et al., 2020) . Some GPCRs (GPR40 and GPR120), which are activated by several fatty acids, including palmitic acid esters of hydroxystearic acids (PAHSAs) in mice and human models, are targets of type II diabetes therapies (Syed et al., 2018; Yore et al., 2014) . In neutrophils, short-chain fatty acids engage with GPR43, inducing chemotaxis (Vinolo et al., 2011) . Thus, the binding of metabolites to proteins, such as receptors, induces specific cellular responses, leading to the activation of specific signaling pathways. Additionally, metabolites are related to prions. The cellular prion protein, PrP c is a cell-surface glycoprotein anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). PrP c is found in mammalian tissues, mostly in neuronal cells, despite some evidence of its involvement in signal transduction (Bate et al., 2016; Mouillet-Richard et al., 2000) , memory formation, peripheral myelin maintenance, circadian rhythm neuroprotection, and immune system activation (Dearmond et al., 1999; Ermonval, Mouillet-Richard, Codogno, Kellermann, & Botti, 2003) . Although the exact role of PrP c is not well defined, it is well known that PrP c is the pathology of its misfolded isoform related to disease, PrP sc . This isoform can aggregate with other PrP molecules, causing a fatal neurodegenerative process (Ermonval et al., 2003) . Glycosylation is strongly related to glucose and glutamine metabolism (Carvalho-cruz et al., 2018) : it is the most important posttranslational modification of PrP. Unglycosylated PrP has been reported to induce apoptosis in oral squamous cell carcinoma and colon adenocarcinoma (Yap & Say, 2011) . Another study reported that glycosylation is important for determining the PrP location on the membrane, to inhibit its aggregation and diminish its cytotoxicity by lowering the intracellular levels of reactive oxygen species (ROS) (Yi et al., 2018) . In 2012, Koonin refuted the "central dogma" idea that information cannot be transferred from proteins to the genome. This refutation is based on the genetic assimilation of prion-dependent phenotypic heredity, which is mediated by epigenetic mechanisms. He named it the "general look-ahead effect" (Koonin, 2012) . Conventionally, epigenetic modifications comprise all aspects of the chromatin structure, histone posttranslational modifications, RNA, DNA methylation, or hydroxymethylation, and metabolites act as the substrates for these modifications (Carrer & Wellen, 2014; Gerhäuser, 2012; Janke et al., 2015; Johnson et al., 2015; Petersen et al., 2014; Roberti et al., 2021) . In 1942, Waddington introduced the concept of epigenetics. He defined internal and external interactions between genes and their products, leading to the development of phenotypes (Waddington, 1942) . In recent years, this concept has been slightly updated to the most accepted definition: "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence" (Robertson, 2005) . Posttranslational modifications of histones are involved in the repression or activation of gene transcriptions and can be linked to DNA methylation. One good example is histone acetylation, through an acetyl donor, the metabolite acetyl-CoA, which modifies the chromatin structure and creates an accessible structure that is beneficial for transcription. The availability of the metabolite acetate and its pathway is important for maintaining acetylation levels (Di Cerbo & Schneider, 2013; Pogo et al., 1966; Turner & O'Neill, 1995; Wolfe, 2005) . In addition, histone acetylation is responsible for generating binding sites that are recognized by bromodomain-containing regulators, promoting gene activation (Filippakopoulos & Knapp, 2014; Shogren-Knaak et al., 2006) . Acetate supplementation restored chromatin accessibility in a neuroblastoma differentiation model (Li et al., 2020a (Li et al., , 2020b . Lauterbach et al. observed that in macrophages, lipopolysaccharide (LPS) signaling promotes the incorporation of acetyl-CoA into histones through an increased glycolytic flux and ATP-citrate lyase activity. This histone acetylation induces specific gene sets associated with proinflammatory responses (Lauterbach et al., 2019) . In addition to acetyl-CoA, there are other metabolites responsible for posttranslational modifications, such as succinyl-CoA (succinylation) and sugar molecules, such as uridine 5′-diphosphoglucose (UDP-glucose) (glycosylation and GlcNAcylation). Succinylation was observed to mediate the mitochondrial translocation of pyruvate kinase M2 (PKM2), thereby playing a role in switching the cellular machinery from proliferation to cell survival mode and vice versa in cancer cells (Qi et al., 2019) . In macrophages, Lys311 is a key succinylated site in the regulation of PKM2 activity, promoting inflammation (Wang et al., 2017) . O-GlcNAcylation plays an important role in the regulation of cellular signaling, translation, and transcription in response to nutrients and stresses (Li et al., 2019; Ong et al., 2018) ; glycosylation is important in the correct folding and trafficking of proteins, such as Relmα, CD206, and CD301, which are destined for secretion or exportation to the cell surface in anti-inflammatory macrophages (Jha et al., 2015) . In addition, α-ketoglutarate and flavin adenine dinucleotide (FAD) from the tricarboxylic acid cycle (TCA) increase DNA demethylase, while succinate and fumarate function as antagonists to inhibit such demethylases, thus demonstrating the pivotal role of TCA in epigenetic reprogramming (Xiao et al., 2012) and tumorigenesis (Kaelin & McKnight, 2013; Martínez-Reyes & Chandel, 2020; Soga, 2013) . Previous studies have demonstrated that mutations in metabolic enzymes, such as succinate dehydrogenase, fumarate hydratase, and NADP+-dependent isocitrate dehydrogenase (both cytosolic and mitochondrial) favor the generation of oncometabolites through the accumulation of succinate and fumarate, triggering hypermethylation of DNA (Eijkelenkamp et al., 2020; Mohammad et al., 2020; Parsons et al., 2008; Ward et al., 2010; Zhu et al., 2020) . Methylation and demethylation are key modifications of histones, DNA, and RNA; they play an important role in the regulation of gene expression and are essential for cell differentiation and embryonic development (Bachman et al., 2014; Petkovich et al., 2017) . In this process, the methyl group of the metabolite, S-adenosylmethionine (SAM), is donated to the methyl transferase enzymes (Warth et al., 2017) . DNA methylation is strongly associated with histone deacetylases (HDACs), leading to chromatin inactivation (Tiwari et al., 2008) . In addition, methylation turnover can differ within the genome (Ginno et al., 2020) . Epitranscriptomics has been shown to be extremely important. Among 170 epigenetic modifications in coding and noncoding RNAs (Boccaletto et al., 2018) , N 6 -methyladenosine methylation (m 6 A) is the most studied (Zaccara et al., 2019b) . Some proteins recognize this RNA modification and mediate several functions, such as mRNA splicing, stability, microRNA processing, and translation (Meyer & Jaffrey, 2017; Shi et al., 2019; Zaccara et al., 2019a) . In addition, m 6 A is linked to diverse biological functions, such as cancer , T cell differentiation (Furlan et al., 2019) , and skin morphogenesis (Xi et al., 2020) . The association of metabolites with metabolic states can enable the formation of metabolic signatures. Furthermore, the identification of the relationships between metabolites and enzyme activity, nutrient import, and posttranslational modifications (Table 1 ) reinforces their role in phenotype acquisition. Changes in the extracellular environment, such as food deprivation, caloric restriction, and intense exercise, modify intracellular nutrient-responsive pathways that promote adaptation and epigenetic changes (Dai et al., 2020; Gut & Verdin, 2013; Pizzorusso & Tognini, 2020) . Diet and lifestyle are important external factors that can affect metabolomics and, consequently, the phenotype. Vitamin D is mainly produced through endogenous production; however, through the lifestyle factor, solar ultraviolet-B radiation (UV-B) irradiates 7-dehydrocholesterol present in the skin to generate cholecalciferol (Pilz et al., 2013) , which is subsequently activated in the liver and kidney. The other source of vitamin D is dietary intake, which includes supplementation with ergocalciferol or cholecalciferol. Most of the biological functions of the active metabolite of vitamin D are mediated through the regulation of gene expression. The 1,25 dihydroxyvitamin D (1,25(OH) 2 D 3 ) binds to its nuclear receptor (nVDR) with high affinity and specificity, forming a heterodimer with the retinoid X receptor. Thus, this complex can repress or amplify the transcription of target genes. This occurs through its binding to vitamin D-responsive elements in DNA (Pilz et al., 2013) . nVDR is found in some immune cells, such as monocytes and macrophages (Neve et al., 2014) . Thus, the active metabolite of vitamin D has an anti-inflammatory effect on macrophages, modifying the phenotype, and downregulating the expression and production of several proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-8 (Giulietti et al., 2007) , in different diseases, such as COVID-19 (Jain et al., 2020) , hepatic inflammation and steatosis (Dong et al., 2020) . Folate, choline, and methionine are essential metabolites related to methylation through the conversion of homocysteine to SAM. These metabolites are dietary requirements for maintaining methylation levels (Elango, 2020; Niculescu & Zeisel, 2002; Pizzorusso & Tognini, 2020) . A methyldeficient diet reduces one-third of the remethylation of one-carbon cycle metabolites (Farias et al., 2015; Ferrari & Pasini, 2013; Gerhäuser, 2012; Townsend, Davis, Mackey, & Gregory, 2004 ) and leads to aberrant DNA-methyltransferase activity, abnormal DNA methylation in liver tumors (Lopatina, 1998) , and RNA methylation (Mosca et al., 2019) . In addition to dietary sources, folate can be synthesized by small intestine flora, and most of it is absorbed by the host (Camilo et al., 1996) . Betaine supplementation can enhance the levels of mRNA methylation and decrease fat mass and obesity-associated (FTO) expression in mice on a high-fat diet (Zhou et al., 2015) . The presence of selenium in the culture media affects the methylation levels of selenocysteine tRNAs (Diamond et al., 1993) . Among the metabolites, β-hydroxybutyrate (β-OHB), a ketone body delivered by the liver during fasting or prolonged exercise, reshapes DNA by inhibiting HDACs (Mikami et al., 2020; Shimazu et al., 2013) . After 12 h of fasting, the intake of ketogenic diets, or prolonged intense exercises, high circulation levels of β-OHB reach 1-2 mM (Koeslag, Noakes, & Sloan, 1980) . β-OHB acts through GPR109, a GPCR that binds short-chain fatty acids. Such actions inhibit class I HDACs, which regulate gene expression through the deacetylation of lysine residues on histone and nonhistone proteins (Newman & Verdin, 2014) . β-OHB increases the intracellular content of acetyl-CoA, indirectly altering histone acetylation by promoting acetyltransferase activity via an acetyl-CoA flux (Ku et al., 2020; Xie et al., 2012) . Furthermore, histone hyperacetylation triggered by β-OHB results in the increased expression of forkhead box O3 (FOXO3) (Kenyon, 2010) . The increase in FOXO3 and metallothionein promoted by the hyperacetylation of histone H3 on lysine 9 (H3K9) offers resistance to oxidative stress (Shimazu et al., 2013; Xie et al., 2016) . Tanegashima et al. demonstrated that fasting induces H3K9 acetylation in the enhancer region of the Slc2a1 gene Provide substrates for the synthesis of lipids, such as diacylglycerol (DAG) and ceramides; TLR4 mediated activation of inhibitors of nuclear factor-kβ (NF-kβ) kinase subunit-β (IKKβ) and Jun N-terminal kinase (JNK) Impairment of insulin sensitivity through IKKβ and JNK-mediated phosphorylation of IRS1 on Ser307; increased production of proinflammatory cytokines Yang et al. (2018) Polyunsaturated fatty acids (PUFAs) Activation of GPCR120 Recruitment of β-arrestin 2, which sequesters TAK1-binding protein (TAB1), triggering the inhibition of MAP3K7 to prevent JNK and IKKβ activity and resulting in anti-inflammatory effects Yang et al. (2018) Palmitic acid esters of hydroxystearic acid (PAHSAs) Activation of the long form of GPCR120 Enhanced insulin-stimulated GLUT4 translocation to membraneYore et al. (2014) Acetyl-CoA Acetylation of IRS proteins in lysine residues by the histone acetyltransferase, p300 Impaired insulin signaling Cao et al. (2017) Acetylation of AKT at lys14 and lys20 by p300 and the p300/CBP-associated factor (P/CAF) Blockage of AKT binding to phosphatidylinositol (3,4,5)-triphosphate (PIP3) at the plasma membrane Sundaresan et al. (2011) Deacetylation of AKT at lys14 and lys20 by SIRT1 AKT activation through AKT-PIP 3 binding Sundaresan et al. (2011) Acetylation of glucosamine-6-phosphate Synthesis of uridine-diphosphate-GlcNac Yang and Qian (2017) Palmitate Palmitoylation of GLUT4 at Cy223 Insulin-stimulated GLUT4 translocation to membrane Du et al. (2017) β-OHB Inhibition of HDAC1 and HDAC2 activity Increase in histone acetylation at promoters of FOXO3 and metallothionein 2 resulting in protection against oxidative stress Shimazu et al. (2013) Metabolites and solute carrier transporters Metabolite condition Transporter modulation Cellular effect Glucose starvation Induction of SLC7A11 expression Uptake of cystine by SLC7A11 transporters depleting intracellular NADPH and inducing ROS, triggering cancer cell death under glucose starvation Koppula et al. (2017 ), Shin et al. (2017 Cystine deprivation, oxidative stress Induction of SLC7A11 expression via nuclear factor erythroid 2-related factor 2 (NRF2) and activating transcription factor 4 (ATF4) Import of cystine and reestablishment of redox balance Koppula et al. (2018) in neuronal and endothelial cells, due to increased levels of β-OHB. This further maintains a constant glucose concentration in the brain during fasting (Tanegashima et al., 2017) . In contrast, supplementation with ketone esters has recently been shown to inhibit glycolysis in the brains of nonfasted mice (Suissa et al., 2021) . In addition to β-OHB, other metabolites are required for enzymes capable of modifying DNA or histones, and during fasting or energy scarcity, the intracellular levels of nicotinamide adenine nucleotide (NAD+), an energy carrier, increase. This metabolite is a cofactor for sirtuin and poly (ADP-ribose) polymerases (PARP), which regulate cellular functions ranging from gene expression to fatty acid metabolism. Once NAD+ levels increase during fasting or energy scarcity, this reflects the potential of such metabolites to regulate intracellular processes in response to environmental changes (Katsyuba et al., 2020; Verdin, 2015) . It was previously demonstrated that food bioactive compounds, such as sulforaphane, a thiocyanate particularly found in broccoli, increase VDR expression (Apprato et al., 2020) , inhibit HDAC activity (Tortorella et al., 2015) , and increase histone H3 and H4 acetylation (Juge et al., 2007) . Furthermore, sulforane cysteine, sulforane N-acetyl-cysteine, allyl mercaptan, and diallyl disulfide, the metabolites produced by microbial metabolism of cruciferous vegetables and garlic induce epigenetic changes by inhibiting histone deacetyl transferase enzymes (Kim et al., 2010) . It is well known that the intestinal microbiota is sensitive to environmental changes, such as high-fat diets (David et al., 2014; Peng et al., 2021) , micronutrient deficiency (Hibberd et al., 2017) , obesity (Aron-Wisnewsky et al., 2021; Turnbaugh et al., 2009) , and chronic inflammation (Couto et al., 2020; Round & Mazmanian, 2009 ). Therefore, modulating the microbiome maintains and/or improves health through the metabolites produced by intestinal microorganisms in response to the components of the diet, thus resulting in the production of short-chain fatty acids (SCFA), such as butyrate, acetate, and propionate (Guilloteau et al., 2010) . In addition, SCFAs are produced through the fermentation of nondigestible carbohydrates, such as dietary fibers, which activate GPCRs, such as GPR41 and GPR43, leading to the inhibition of HDACs (Bhat & Kapila, 2017) . Food bioactive compounds can interact directly with DNA, and dietary behavior can affect DNA structure, leading to a different phenotype. For example, three flavonoids, quercetin, kaempferol, and delphinidin can bind to adenine and guanine (major groove), and thymine (minor groove) (Kanakis et al., 2005) , and saffron derivate metabolites can interact with DNA guanine-quadruplexes (G4) (Hoshyar et al., 2012) . These G4 motifs are stable structures related to gene promoter regulation and DNA methylation (Hardin et al., 1993; Mao et al., 2018) ; they can be dysregulated by aberrant DNA methylation due to folate deprivation Low levels of butyric acid in the gut Downregulation of SLC16A1 Decreased transport of butyric acid Thibault et al. (2007) mTORC complex Increased GLUT1 expression Downstream aerobic glycolysis in T cells to support their proliferation and effector function Song et al. (2020) (Tavakoli Shirazi et al., 2018) . Upon interfering with the genome, all other steps of the flux of information will be affected, including the phenotype. Metabolites can induce macromolecule activity and control phenotypes. It has been shown that omics-scale techniques provide better correlation than single approaches, which indicates that the "central dogma" is a wide integration of information (Piras et al., 2012) . Recently, Bar et al. analyzed 1251 metabolites from the serum of 491 individuals and by machine learning deduced that the diet and microbiome both represent 50% of an individual's metabolic profile (Bar et al., 2020) . This concept is a paradigm shift in that it reshapes the conventional thinking about the molecular linear "central dogma," placing metabolomics at the center, not only providing a simple readout to other omics, but also acting as a master regulator of the whole system (Guijas et al., 2018) . Acknowledgements The authors thank Professor Tatiana El-Bacha for the rich discussion in this article. We would like to thank Editage (www. edita ge. com) for English language editing. Author contributions GCS conceived and designed the ideas of this study. MRM and NMB developed some parts of the text and reviewed the paper. Funding Not applicable. Data availability Not applicable. Code availability Not applicable. The authors declare that they have no conflict of interest. Ethical approval Not applicable. Research involving human participants and/or animals GCS, MRM and NMB complied with Springer's ethical policies. This article does not contain any studies with human or animal subjects performed by any of the authors. Consent for publication Not applicable. Metabolomics platforms for genome wide association studies-Linking the genome to the metabolome Integrative clinical, genomics and metabolomics data analysis for mainstream precision medicine to investigate COVID-19 Genome-wide localization of small molecules Natural epigenetic modulators of vitamin D receptor Metabolism and metabolic disorders and the microbiome: The intestinal microbiota associated with obesity, lipid metabolism, and metabolic health-Pathophysiology and therapeutic strategies 5-Hydroxymethylcytosine is a predominantly stable DNA modification A reference map of potential determinants for the human serum metabolome Sialic acid on the glycosylphosphatidylinositol anchor regulates PrP-mediated cell signaling and prion formation Metabolomics enables precision medicine Trimethylamine-N-Oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation An overview of recent advances in duplex DNA recognition by small molecules Dietary metabolites derived from gut microbiota: Critical modulators of epigenetic changes in mammals Plasma membrane subdomain compartmentalization contributes to distinct mechanisms of ceramide action on insulin signaling MODOMICS: A database of RNA modification pathways. 2017 update Folate synthesized by bacteria in the human upper small intestine is assimilated by the host Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity Metabolism and epigenetics: A link cancer cells exploit Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition Serine is a natural ligand and allosteric activator of pyruvate kinase M2 Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis Heme oxygenase metabolites improve astrocytic mitochondrial function via a Ca2+-dependent HIF-1α/ERRα circuit 60 years ago, Francis Crick changed the logic of biology Saliva NMR-based metabolomics in the war against COVID-19 Microbiota-derived butyrate regulates intestinal inflammation: Focus on inflammatory bowel disease On protein synthesis The evolving metabolic landscape of chromatin biology and epigenetics Systems metabolomics: From metabolomic snapshots to design principles Diet rapidly and reproducibly alters the human gut microbiome Normal and osteoarthritic synovial fluid present different metabolomic profile Metabolomics as a promising tool for early osteoarthritis diagnosis Osteoarthritic synovial fluid modulates cell phenotype and metabolic behavior in vitro PrP(c) glycoform heterogeneity as a function of brain region: Implications for selective targeting of neurons by priori strains Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis Covid-19 automated diagnosis and risk assessment through metabolomics and machine learning Protonation of trimethylamine N-oxide (TMAO) is required for stabilization of RNA tertiary structure Molecular recognition of DNA by small molecules Cancers with wrong HATs: The impact of acetylation Dietary selenium affects methylation of the wobble nucleoside in the anticodon of selenocysteine tRNA Vitamin D receptor activation in liver macrophages ameliorates hepatic inflammation, steatosis, and insulin resistance in mice Metabolomics in cancer and cancer-associated inflammatory cells DHHC7 palmitoylates glucose transporter 4 (Glut4) and regulates Glut4 membrane translocation Clinical implications of the oncometabolite succinate in SDHx-mutation carriers Methionine nutrition and metabolism: Insights from animal studies to inform human nutrition Evolving views in prion glycosylation: Functional and pathological implications Interplay between metabolism and epigenetics: A nuclear adaptation to environmental changes The effects of folic acid on global DNA methylation and colonosphere formation in colon cancer cell lines Regulation and function of DNA and histone methylations Targeting bromodomains: Epigenetic readers of lysine acetylation Oncogene expression modulation in cancer cell lines by DNA G-quadruplex-interactive small molecules M6A-dependent RNA dynamics in T cell differentiation Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia Cancer cell metabolism, epigenetics and the potential influence of dietary components-A perspective The association of fish consumption and its urinary metabolites with cardiovascular risk factors: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D3 works as anti-inflammatory AMP is a true physiological regulator of amp-activated protein kinase by both allosteric activation and enhancing net phosphorylation Metabolomics activity screening for identifying metabolites that modulate phenotype From the gut to the peripheral tissues: The multiple effects of butyrate The nexus of chromatin regulation and intermediary metabolism Cytosine-Cytosine+ base pairing stabilizes DNA quadruplexes and cytosine methylation greatly enhances the effect The effects of micronutrient deficiencies on bacterial species from the human gut microbiota Is there any interaction between telomeric DNA structures, G-quadruplex and I-motif, with Saffron active metabolites? Nucleosides, Nucleotides and Nucleic Acids Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging Trimethylamine N-oxide influence on the backbone of proteins: An oligoglycine model Pyruvate kinase: Function, regulation and role in cancer Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers Metabolism and epigenetics Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization Xenobiotic metabolomics: Major impact on the metabolome Epigenetics and cancer metabolism Molecular basis for chemoprevention by sulforaphane: A comprehensive review Influence of metabolism on epigenetics and disease Dna interaction with naturally occurring antioxidant flavonoids quercetin, kaempferol, and delphinidin NAD+ homeostasis in health and disease The genetics of ageing Dietary, metabolic, and potentially environmental modulation of the lysine acetylation machinery Metabolism, epigenetics, and causal inference in heart failure Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood The deep sea osmolyte trimethylamine N-oxide and macromolecular crowders rescue the antiparallel conformation of the human telomeric G-quadruplex from urea and pressure stress Metabolic plasticity in CLL: Adaptation to the hypoxic niche Post-exercise ketosis Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein Does the central dogma still stand The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer Metabolic engineering design strategies for increasing acetyl-coa flux The osmolyte TMAO stabilizes native RNA tertiary structures in the absence of Mg2+: Evidence for a large barrier to folding from phosphate dehydration Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase O-GlcNAcylation in immunity and inflammation: An intricate system (Review). International Integrated omics analysis reveals the alteration of gut microbemetabolites in obese adults Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis Toward a standardized strategy of clinical metabolomics for the advancement of precision medicine Elevated expression and altered pattern of activity of DNA methyltransferase in liver tumors of rats fed methyldeficient diets Bioactivity of dietary polyphenols: The role of metabolites DNA G-quadruplex structures mold the DNA methylome A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model Mitochondrial TCA cycle metabolites control physiology and disease Effects of urea and trimethylamine-N-oxide on enzyme activity and stability Metabolomics: The apogee of the omics trilogy Rethinking m6A readers, writers, and erasers β-Hydroxybutyrate enhances the cytotoxic effect of cisplatin via the inhibition of HDAC/ survivin axis in human hepatocellular carcinoma cells Characterisation of isocitrate dehydrogenase 1/ isocitrate dehydrogenase 2 gene mutation and the d-2-hydroxyglutarate oncometabolite level in dedifferentiated chondrosarcoma Nutrigenomics and RNA methylation: Role of micronutrients Signal transduction through prion protein Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects Slotting metabolomics into routine precision medicine. Expert Review of Precision Medicine and Drug Development DNA minor-groove recognition by small molecules Immunomodulatory effects of vitamin D in peripheral blood monocyte-derived macrophages from patients with rheumatoid arthritis Ketone bodies as signaling metabolites Diet, methyl donors and DNA methylation: Interactions between dietary folate, methionine and choline O-GlcNAc as an integrator of signaling pathways Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development An integrated genomic analysis of human glioblastoma multiforme A multi-omics interpretable machine learning model reveals modes of action of small molecules Innovation: Metabolomics: The apogee of the omics trilogy Helicobacter pylori infection worsens impaired glucose regulation in high-fat diet mice in association with an altered gut microbiome and metabolome Epigenetics meets metabolomics: An epigenome-wide association study with blood serum metabolic traits Using DNA methylation profiling to evaluate biological age and longevity interventions Role of vitamin D in the development of insulin resistance and type 2 diabetes Is central dogma a global property of cellular information flow? Interplay between metabolism, nutrition and epigenetics in shaping brain dna methylation, neural function and behavior RNA synthesis and histone acetylation during the course of gene activation in lymphocytes Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/ methyl-deficient diet Succinylation-dependent mitochondrial translocation of PKM2 promotes cell survival in response to nutritional stress Metabolite turns master regulator The impact of cellular metabolism on chromatin dynamics and epigenetics Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation Epigenetic Mechanisms of Gene Regulation. In: DNA Methylation and Cancer Therapy Enhanced OXPHOS, glutaminolysis and β-oxidation constitute the metastatic phenotype of melanoma cells Unravelling the genomic targets of small molecules using high-throughput sequencing Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes The gut microbiota shapes intestinal immune responses during health and disease Metabolic profile of oral squamous carcinoma cell lines relies on a higher demand of lipid metabolism in metastatic cells Metabolomic analysis reveals vitamin D-induced decrease in polyol pathway and subtle modulation of glycolysis in HEK293T cells Small molecules: The missing link in the central dogma Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogenactivated protein kinase and nuclear factor-κb Where, when, and how: Contextdependent functions of RNA methylation writers, readers, and erasers Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility Histone H4-K16 acetylation controls chromatin structure and protein interactions Cancer metabolism: Key players in metabolic reprogramming Solute carrier transporters: The metabolic gatekeepers of immune cells Ingested ketone ester leads to a rapid rise of acetyl-coa and competes with glucose metabolism in the brain of non-fasted mice The role of m6A RNA methylation in cancer The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease Folate modulates guanine-quadruplex frequency and DNA damage in Werner syndrome Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation Background diet influences TMAO concentrations associated with red meat intake without influencing apparent hepatic TMAO-related activity in a porcine model Trimethylamine N-oxide (TMAO), diet and cardiovascular disease. Current Atherosclerosis Reports PcG proteins, DNA methylation, and gene repression by chromatin looping Dietary sulforaphane in cancer chemoprevention: The role of epigenetic regulation and HDAC inhibition. Antioxidants and Redox Signaling Folate deprivation reduces homocysteine remethylation in a human intestinal epithelial cell culture model: Role of serine in one-carbon donation A core gut microbiome in obese and lean twins Histone acetylation in chromatin and chromosomes Epigenitics and metabolism in health and disease Effects of trimethylamine N-oxide and urea on DNA duplex and G-quadruplex TMAO: A small molecule of great expectations Secondgeneration DNA-templated macrocycle libraries for the discovery of bioactive small molecules NAD+ in aging, metabolism, and neurodegeneration SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor The epigenotype. Endeavour SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1β production and to prevent DSS-induced colitis in mice The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate Metabolomics reveals that dietary xenoestrogens alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy How metabolites modulate metabolic flux Targeting RNA with small molecules HMDB 4.0: The human metabolome database for 2018 The acetate switch M6a rna methylation impacts fate choices during skin morphogenesis. eLife Inhibition of α-KGdependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors Lysine succinylation and lysine malonylation in histones Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation A metabolite array technology for precision medicine Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutaratedependent dioxygenases Protein O-GlcNAcylation: Emerging mechanisms and functions Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth Metabolites as regulators of insulin sensitivity and metabolism Resistance against apoptosis by the cellular prion protein is dependent on its glycosylation status in oral HSC-2 and colon LS 174T cancer cells Glycosylation significantly inhibits the aggregation of human prion protein and decreases its cytotoxicity Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects Metabolism as a signal generator across trans-omic networks at distinct time scales. Current Opinion in Systems Biology Reading, writing and erasing mRNA methylation Reading, writing and erasing mRNA methylation Trimethylamine N-oxide, the microbiome, and heart and kidney disease The SLC transporter in nutrient and metabolic sensing, regulation, and drug development Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization Zhou, X., Chen, J., Chen, J., Wu, W., Wang, X., & Wang, Y. (2015) .The beneficial effects of betaine on dysfunctional adipose tissue and N6-methyladenosine mRNA methylation requires the AMPactivated protein kinase α1 subunit. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.