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Journal of Biochemistry Jan 2019The central dogma of molecular biology explains the fundamental flow of genetic information for life. Although genome sequence (DNA) itself is a static chemical... (Review)
Review
The central dogma of molecular biology explains the fundamental flow of genetic information for life. Although genome sequence (DNA) itself is a static chemical signature, it includes multiple layers of information composed of mRNA, tRNA, rRNA and small RNAs, all of which are involved in protein synthesis and is passing from parents to offspring via DNA. Methylation is a biologically important modification, because DNA, RNAs and proteins, components of the central dogma, are methylated by a set of methyltransferases. Recent works focused on understanding a variety of biological methylation have shed light on new regulation of cellular functions. In this review, we briefly discuss some of those recent findings of methylation, including DNA, RNAs and proteins.
Topics: Animals; Arginine; DNA; DNA Methylation; Demethylation; Humans; Lysine; Methylation; Methyltransferases; Protein Biosynthesis; Proteins; RNA
PubMed: 30219914
DOI: 10.1093/jb/mvy075 -
Hormones and Behavior May 2023Some of the best-studied neural sex differences depend on differential cell death in males and females, but other sex differences persist even if cell death is...
Some of the best-studied neural sex differences depend on differential cell death in males and females, but other sex differences persist even if cell death is prevented. These include sex differences in neurochemical phenotype (i.e., stable patterns of gene expression). Work in our laboratory over the last several years has tested the hypothesis that sex differences in DNA methylation early in life underlie sexual differentiation of neuronal phenotype. We have shown that 1) expression of enzymes that place or remove DNA methylation marks is greatest during the first week of life in the mouse brain and overlaps with the perinatal critical period of sexual differentiation; 2) a transient inhibition of DNA methylation during neonatal life abolishes several sex differences in cell phenotype in the mouse hypothalamus; 3) both DNA methylation and de-methylation contribute to the development of neural sex differences; and 4) the effects of DNA methylation and de-methylation are brain region- and cell type-specific.
Topics: Animals; Mice; Female; Male; DNA Methylation; Sex Differentiation; Phenotype; Neurons; Demethylation
PubMed: 37001316
DOI: 10.1016/j.yhbeh.2023.105349 -
Pharmacology Research & Perspectives Feb 2021Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological... (Clinical Trial)
Clinical Trial
Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites.
Topics: Administration, Oral; Antiparasitic Agents; Cells, Cultured; Cytochrome P-450 Enzyme System; Demethylation; Hepatocytes; Humans; Hydroxylation; Ivermectin; Metabolic Networks and Pathways; Microsomes, Liver
PubMed: 33497030
DOI: 10.1002/prp2.712 -
Cellular and Molecular Biology... Mar 2023TET2 is a member of the TET protein family which is responsible for active DNA demethylation through catalyzing the successive oxidation of 5-methylcytosine (5mC) to...
TET2 is a member of the TET protein family which is responsible for active DNA demethylation through catalyzing the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), and mutations of Tet2 frequently lead to hematological malignancies. However, the relationship between Tet2-mediated demethylation and hematological malignancies is unclear. The human leukemia K562 cell line is an immortalized leukemia line that serves as an in vitro model of erythroleukemia. In this study, we investigated the effect of Tet2-mediated demethylation on the apoptosis and proliferation of human leukemia K562 cells and found that knockdown of Tet2 promoted and inhibited K562 cell proliferation and apoptosis, respectively, while upregulation of TET2 enzymatic activity via alpha-ketoglutaric acid (α-KG) had the opposite effects. Therefore, the Tet2 gene acts as a potential target for the treatment of leukemia, and small molecules that target the Tet2 gene may be used to screen antitumor drugs for hematological malignancies.
Topics: Humans; Apoptosis; Dioxygenases; DNA Demethylation; DNA Methylation; DNA-Binding Proteins; Hematologic Neoplasms; K562 Cells; Leukemia
PubMed: 37300692
DOI: 10.14715/cmb/2023.69.3.4 -
The New England Journal of Medicine Aug 2022
Topics: Azacitidine; Demethylation; Humans; Myelodysplastic Syndromes; Oncogenes; Up-Regulation
PubMed: 35921466
DOI: 10.1056/NEJMc2208134 -
Journal of Hazardous Materials Oct 2023The production of methylmercury (MeHg) in flooded paddy fields determines its accumulation in rice grains; this, in turn, results in MeHg exposure risks for not only...
The production of methylmercury (MeHg) in flooded paddy fields determines its accumulation in rice grains; this, in turn, results in MeHg exposure risks for not only rice-eating humans but also wildlife. Nitrogen (N) fertilizers have been widely applied in rice cultivation fields to supply essential nutrients. However, the effects of N fertilizer addition on mercury (Hg) transformations are not unclear. This limits our understanding of MeHg formation in rice paddy ecosystems. In this study, we spiked three Hg tracers (Hg, MeHg, and Hg) in paddy slurries fertilized with urea, ammonium, and nitrate. The influences of N fertilization on Hg methylation, demethylation, and reduction and the underlying mechanisms were elucidated. The results revealed that dissimilatory nitrate reduction was the dominant process in the incubated paddy slurries. Nitrate addition inhibited Hg reduction, Hg methylation, and MeHg demethylation. Competition between nitrates and other electron acceptors (e.g., Hg, sulfate, or carbon dioxide) under dark conditions was the mechanism underlying nitrate-regulated Hg transformation. Ammonium and urea additions promoted Hg reduction, and anaerobic ammonium oxidation coupled with Hg reduction (Hgammox) was likely the reason. This work highlighted that nitrate addition not only inhibited Hg methylation but also reduced the demethylation of MeHg and therefore may generate more accumulation of MeHg in the incubated paddy slurries. Findings from this study link the biogeochemical cycling of N and Hg and provide crucial knowledge for assessing Hg risks in intermittently flooded wetland ecosystems.
Topics: Humans; Nitrates; Mercury; Methylation; Ecosystem; Methylmercury Compounds; Urea; Fertilizers; Oryza; Demethylation
PubMed: 37669605
DOI: 10.1016/j.jhazmat.2023.132457 -
Cell Reports Mar 2020Histone methyl groups can be removed by demethylases. Although LSD1 and JmjC domain-containing proteins have been identified as histone demethylases, enzymes for many...
Histone methyl groups can be removed by demethylases. Although LSD1 and JmjC domain-containing proteins have been identified as histone demethylases, enzymes for many histone methylation states or sites are still unknown. Here, we perform a screening of a cDNA library containing 2,500 nuclear proteins and identify hHR23A as a histone H4K20 demethylase. Overexpression of hHR23A reduces the levels of H4K20me1/2/3 in cells. In vitro, hHR23A specifically demethylates H4K20me1/2/3 and generates formaldehyde. The enzymatic activity requires Fe(II) and α-ketoglutarate as cofactors and the UBA domains of hHR23A. hHR23B, a protein homologous to hHR23A, also demethylates H4K20me1/2/3 in vitro and in vivo. We further demonstrate that hHR23A/B activate the transcription of coding genes by demethylating H4K20me1 and the transcription of repetitive elements by demethylating H4K20me3. Nuclear magnetic resonance (NMR) analyses demonstrate that an HxxxE motif in the UBA1 domain is crucial for iron binding and demethylase activity. Thus, we identify two hHR23 proteins as histone demethylases.
Topics: Cell Cycle; DNA Repair Enzymes; DNA-Binding Proteins; Demethylation; Formaldehyde; Genetic Loci; Genome, Human; HEK293 Cells; HeLa Cells; Histones; Humans; Iron; Lysine; Peptides; Protein Domains; RNA, Messenger; Repetitive Sequences, Nucleic Acid; Substrate Specificity; Transcription, Genetic
PubMed: 32209475
DOI: 10.1016/j.celrep.2020.03.001 -
The New Phytologist Feb 2022The ripening of fleshy fruits is a unique developmental process that Arabidopsis and rice lack. This process is driven by hormones and transcription factors. However,...
The ripening of fleshy fruits is a unique developmental process that Arabidopsis and rice lack. This process is driven by hormones and transcription factors. However, the critical and early regulators of fruit ripening are still poorly understood. Here, we revealed that SlJMJ7, an H3K4 demethylase, is a critical negative regulator of fruit ripening in tomato. Combined genome-wide transcription, binding sites, histone H3K4me3 and DNA methylation analyses demonstrated that SlJMJ7 regulates a key group of ripening-related genes, including ethylene biosynthesis (ACS2, ACS4 and ACO6), transcriptional regulation (RIN and NOR) and DNA demethylation (DML2) genes, by H3K4me3 demethylation. Moreover, loss of SlJMJ7 function leads to increased H3K4me3 levels, which directly activates ripening-related genes, and to global DML2-mediated DNA hypomethylation in fruit, which indirectly prompts expression of ripening-related genes. Together, these effects lead to accelerated fruit ripening in sljmj7 mutant. Our findings demonstrate that SlJMJ7 acts as a master negative regulator of fruit ripening not only through direct removal of H3K4me3 from multiple key ripening-related factors, but also through crosstalk between histone and DNA demethylation. These findings reveal a novel crosstalk between histone methylation and DNA methylation to regulate gene expression in plant developmental processes.
Topics: DNA; DNA Demethylation; DNA Methylation; Ethylenes; Fruit; Gene Expression Regulation, Plant; Histones; Solanum lycopersicum; Plant Proteins
PubMed: 34729792
DOI: 10.1111/nph.17838 -
Chemosphere Jun 2020Mercury (Hg) transformations in sediments are key factors in the Hg exposure pathway for wildlife and humans yet are poorly characterized in Arctic lakes. As the Arctic...
Mercury (Hg) transformations in sediments are key factors in the Hg exposure pathway for wildlife and humans yet are poorly characterized in Arctic lakes. As the Arctic is rapidly warming, it is important to understand how the rates of Hg methylation and demethylation (wich determine Hg bioavailability) change with temperature in lake sediments. Methylation and demethylation potentials were determined for littoral sediments (2.5 m water depth) in two deep and two shallow lakes in the Canadian Arctic using Hg stable isotope tracers at incubation temperatures of 4, 8, or 16 °C for 24 h. Compared to sediments from other regions, Hg methylation and demethylation potentials in these sediments are low. The maximum depth of the lake from which sediment was collected exerted a stronger influence over methylation potential than sediment Hg concentration or organic matter content; the shallowest lake had the highest Hg methylation potential. Sediments from the shallowest lake also demonstrated the greatest response to the temperature treatments, with significantly higher methylation potentials in the 8 and 16 °C treatments. Sediments from the deep lakes demonstrated greater demethylation potentials than shallow lakes. The methylmercury to total Hg ratio in sediments supported the measured transformation potentials as the lake with the greatest methylation potential had the highest ratio. This study supports previous works indicating that Hg methylation potential may increase as the Arctic warms, but demethylation potential does not respond to warming to the same degree, indicating that Hg methylation may predominate in warming Arctic sediments.
Topics: Arctic Regions; Canada; Demethylation; Environmental Monitoring; Geologic Sediments; Lakes; Mercury; Methylation; Methylmercury Compounds; Water Pollutants, Chemical
PubMed: 32041063
DOI: 10.1016/j.chemosphere.2020.126001 -
Genome Biology Mar 2022DNA demethylation occurs in many species and is involved in diverse biological processes. However, the occurrence and role of DNA demethylation in maize remain unknown.
BACKGROUND
DNA demethylation occurs in many species and is involved in diverse biological processes. However, the occurrence and role of DNA demethylation in maize remain unknown.
RESULTS
We analyze loss-of-function mutants of two major genes encoding DNA demethylases. No significant change in DNA methylation has been detected in these mutants. However, we detect increased DNA methylation levels in the mutants around genes and some transposons. The increase in DNA methylation is accompanied by alteration in gene expression, with a tendency to show downregulation, especially for the genes that are preferentially expressed in endosperm. Imprinted expression of both maternally and paternally expressed genes changes in F hybrid with the mutant as female and the wild-type as male parental line, but not in the reciprocal hybrid. This alteration in gene expression is accompanied by allele-specific DNA methylation differences, suggesting that removal of DNA methylation of the maternal allele is required for the proper expression of these imprinted genes. Finally, we demonstrate that hypermethylation in the double mutant is associated with reduced binding of transcription factor to its target, and altered gene expression.
CONCLUSIONS
Our results suggest that active removal of DNA methylation is important for transcription factor binding and proper gene expression in maize endosperm.
Topics: Alleles; DNA Demethylation; DNA Methylation; Endosperm; Gene Expression; Gene Expression Regulation, Plant; Genomic Imprinting; Transcription Factors; Zea mays
PubMed: 35264226
DOI: 10.1186/s13059-022-02641-x