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Frontiers in Immunology 2024Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires... (Review)
Review
Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.
Topics: Humans; DNA Methylation; Sjogren's Syndrome; Epigenesis, Genetic; Autoimmune Diseases; Gene Expression Regulation
PubMed: 38510251
DOI: 10.3389/fimmu.2024.1289492 -
Philosophical Transactions of the Royal... May 2021Mollusca are the second largest and arguably most diverse phylum of the animal kingdom. This is in sharp contrast to our very limited knowledge concerning epigenetic...
Mollusca are the second largest and arguably most diverse phylum of the animal kingdom. This is in sharp contrast to our very limited knowledge concerning epigenetic mechanisms including DNA methylation in this invertebrate group. Here, we inferred DNA methylation patterns by analysing the normalized dinucleotide CG content in protein-coding sequences and identified DNA methyltransferases (DNMT1 and 3) in published transcriptomes and genomes of 140 species across all eight classes of molluscs. Given the evolutionary age and morphological diversity of molluscs, we expected to find evidence for diverse methylation patterns. Our inferences suggest that molluscs possess substantial levels of DNA methylation in gene bodies as a rule. Yet, we found deviations from this general picture with regard to (i) the CpG observed/expected distributions indicating a reduction in DNA methylation in certain groups and (ii) the completeness of the DNMT toolkit. Reductions were evident in Caudofoveata, Solenogastres, Polyplacophora, Monoplacophora, as well as Scaphopoda. Heterobranchia and Oegopsida were remarkable as they lacked DNMT3, usually responsible for de novo methylation, yet showed signs of DNA methylation. Our survey may serve as guidance for direct empirical analyses of DNA methylation in molluscs. This article is part of the Theo Murphy meeting issue 'Molluscan genomics: broad insights and future directions for a neglected phylum'.
Topics: Animals; DNA Methylation; Mollusca
PubMed: 33813896
DOI: 10.1098/rstb.2020.0166 -
Andrology Sep 2020DNA methylation patterns can show transgenerational inheritance and are influenced by lifestyle and environmental factors. It is suggested that these patterns can be... (Clinical Trial)
Clinical Trial
BACKGROUND
DNA methylation patterns can show transgenerational inheritance and are influenced by lifestyle and environmental factors. It is suggested that these patterns can be changed by assisted reproductive technology.
OBJECTIVES
To evaluate the impact of two different sperm preparation methods, conventional density gradient centrifugation (DGC) vs. density gradient centrifugation followed by magnetic-activated cell sorting (MACS) of non-apoptotic spermatozoa, on sperm DNA methylation profile.
MATERIALS AND METHODS
We analyzed semen of patients included in our IVF treatment program. Half of the semen from each included patient was prepared for ICSI using the DGC method and the other half with DGC followed by MACS. The remaining samples were processed for DNA methylation analysis with reduced representation bisulfite sequencing (RRBS). In addition to the DNA methylation profile, we assessed the morphology and DNA fragmentation of spermatozoa.
RESULTS
RRBS analysis revealed that the average genome-wide methylation level was similar between both groups (DGC vs. MACS group) and ranged from 0.53 to 0.56. Furthermore, RRBS analysis identified 99 differentially methylated regions (DMRs) and 800 differentially methylated positions (DMPs). In the DGC group, 43 DMRs and 392 DMPs were hypermethylated whereas 56 DMRs and 408 DMPs were hypomethylated compared with those in the MACS group. When DMRs and DMPs were annotated to genes, 3 genes associated with imprinting were found: IGF2, PRDM16, and CLF4/BRUNOL4. The percentage of morphologically normal spermatozoa (MACS vs. DGC; 14.0 ± 10.8 vs. 13.2 ± 10.0; P = .335) and of spermatozoa with fragmented DNA of patients with RRBS analysis (22.9 ± 21.1% vs. 34.4 ± 21.2; P = .529) were also similar between groups.
DISCUSSION AND CONCLUSION
Although the average genome-wide level of sperm DNA methylation was similar in both sample groups, a distinctive number of methylation changes were observed in DMR and DMP levels. A larger number of samples should be analyzed and additional sperm preparation methods should be tested to confirm our findings.
Topics: Adult; Centrifugation, Density Gradient; DNA Fragmentation; DNA Methylation; Female; Flow Cytometry; Humans; Male; Sperm Injections, Intracytoplasmic; Spermatozoa; Teratozoospermia; Treatment Outcome
PubMed: 32470185
DOI: 10.1111/andr.12832 -
BMC Genomic Data Apr 2022Breast cancer is one of the most commonly diagnosed cancers. It is associated with DNA methylation, an epigenetic event with a methyl group added to a cytosine paired...
BACKGROUND
Breast cancer is one of the most commonly diagnosed cancers. It is associated with DNA methylation, an epigenetic event with a methyl group added to a cytosine paired with a guanine, i.e., a CG site. The methylation levels of different genes in a genome are correlated in certain ways that affect gene functions. This correlation pattern is known as co-methylation. It is still not clear how different genes co-methylate in the whole genome of breast cancer samples. Previous studies are conducted using relatively small datasets (Illumina 27K data). In this study, we analyze much larger datasets (Illumina 450K data).
RESULTS
Our key findings are summarized below. First, normal samples have more highly correlated, or co-methylated, CG pairs than tumor samples. Both tumor and normal samples have more than 93% positive co-methylation, but normal samples have significantly more negatively correlated CG sites than tumor samples (6.6% vs. 2.8%). Second, both tumor and normal samples have about 94% of co-methylated CG pairs on different chromosomes, but normal samples have 470 million more CG pairs. Highly co-methylated pairs on the same chromosome tend to be close to each other. Third, a small proportion of CG sites' co-methylation patterns change dramatically from normal to tumor. The percentage of differentially methylated (DM) sites among them is larger than the overall DM rate. Fourth, certain CG sites are highly correlated with many CG sites. The top 100 of such super-connector CG sites in tumor and normal samples have no overlaps. Fifth, both highly changing sites and super-connector sites' locations are significantly different from the genome-wide CG sites' locations. Sixth, chromosome X co-methylation patterns are very different from other chromosomes. Finally, the network analyses of genes associated with several sets of co-methylated CG sites identified above show that tumor and normal samples have different patterns.
CONCLUSIONS
Our findings will provide researchers with a new understanding of co-methylation patterns in breast cancer. Our ability to thoroughly analyze co-methylation of large datasets will allow researchers to study relationships and associations between different genes in breast cancer.
Topics: Breast Neoplasms; Cytosine; DNA Methylation; Epigenomics; Female; Humans
PubMed: 35428183
DOI: 10.1186/s12863-022-01046-w -
Journal of the American Chemical Society Jan 2022The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet...
The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.
Topics: Hydrogen; Methylation
PubMed: 35015533
DOI: 10.1021/jacs.1c09412 -
BioEssays : News and Reviews in... Feb 2024Histone modifications play a critical role in the control over activities of the eukaryotic genome; among these chemical alterations, the methylation of lysine K9 in... (Review)
Review
Histone modifications play a critical role in the control over activities of the eukaryotic genome; among these chemical alterations, the methylation of lysine K9 in histone H3 (H3K9) is one of the most extensively studied. The number of enzymes capable of methylating H3K9 varies greatly across different organisms: in fission yeast, only one such methyltransferase is present, whereas in mammals, 10 are known. If there are several such enzymes, each of them must have some specific function, and they can interact with one another. Thus arises a complex system of interchangeability, "division of labor," and contacts with each other and with diverse proteins. Histone methyltransferases specialize in the number of methyl groups that they attach and have different intracellular localizations as well as different distributions on chromosomes. Each also shows distinct binding to different types of sequences and has a specific set of nonhistone substrates.
Topics: Animals; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Methyltransferases; Histones; Methylation; Chromosomes; Schizosaccharomyces; Mammals
PubMed: 38058121
DOI: 10.1002/bies.202300163 -
The Journal of Maternal-fetal &... Dec 2022Hypothyroidism is a systemic metabolic deficiency syndrome caused by a deficiency in thyroid hormone or a decrease in the action of thyroid hormones. It has a high...
BACKGROUND
Hypothyroidism is a systemic metabolic deficiency syndrome caused by a deficiency in thyroid hormone or a decrease in the action of thyroid hormones. It has a high incidence among women of child-bearing age, and pregnant women with hypothyroidism may have a higher risk of birth defects.
OBJECTIVE
To explore the specific biological mechanism affecting the occurrence of hypothyroidism.
METHODS
This study determined key molecules by comparing and analyzing the difference in methylation levels between pre-pregnancy women and normal controls using the Illumina Infinium MethylationEPIC BeadChip.
RESULTS
3493 Differential methylation positions (DMPs) related genes and 47 differentially methylated regions (DMRs) related genes were found between the Hypothyroidism group and the control group. Among them, miR-21 has been found to be closely related to thyroid hormone regulation. The results of enrichment analysis showed that the DMPs or DMRs-related genes are both significantly enriched in human T-cell leukemia virus 1 infection, osteoclast differentiation and sphingolipid signaling pathway, which were also closely related to the occurrence and development of hypothyroidism. In addition, the combined analysis of CNVs and DMRs showed that significant differences occurred near the regions of 16 M bp in chromosome 1 between the two groups, and the genes involved in these regions included NDUFS2, FCER1G and SHC1.
CONCLUSION
This work screened molecular markers and key signaling pathways that are involved in the development of hypothyroidism in pre-pregnancy women, which may provide new targets for the research and diagnosis of hypothyroidism in the future.
Topics: Humans; Female; Pregnancy; Hypothyroidism; DNA Methylation; Pregnancy Complications; Thyroid Hormones
PubMed: 33455507
DOI: 10.1080/14767058.2021.1874907 -
Clinics and Research in Hepatology and... Nov 2020Hepatitis B virus (HBV) chronic infection is responsible for almost 900.000 deaths each year, due to cirrhosis or hepatocellular carcinoma (HCC). Ten HBV genotypes have... (Review)
Review
Hepatitis B virus (HBV) chronic infection is responsible for almost 900.000 deaths each year, due to cirrhosis or hepatocellular carcinoma (HCC). Ten HBV genotypes have been described (A-J). HBV genotype F and H circulate in America. HBV genotypes have been further classified in subgenotypes. There is a strong correlation between the genetic admixture of the American continent and the frequency of genotypes F or H: a high frequency of these genotypes is found in countries with a population with a higher ratio of Amerindian to African genetic admixture. The frequency of occult HBV infection in Amerindian communities from Latin America seems to be higher than the one found in other HBV-infected groups, but its association with American genotypes is unknown. There is growing evidence that some genotypes might be associated with a faster evolution to HCC. In particular, HBV genotype F has been implicated in a frequent and rapid progression to HCC. However, HBV genotype H has been associated to a less severe progression of disease. This study reviews the diversity and frequency of autochthonous HBV variants in the Americas and evaluates their association to severe progression of disease. Although no significant differences were found in the methylation pattern between different genotypes and subgenotypes of the American types, basal core promoter mutations might be more frequent in some subgenotypes, such as F1b and F2, than in other American subgenotypes or genotype H. F1b and probably F2 may be associated with a severe presentation of liver disease as opposed to a more benign course for subgenotype F4 and genotype H. Thus, preliminary evidence suggests that not all of the American variants are associated with a rapid progression to HCC.
Topics: American Indian or Alaska Native; Carcinoma, Hepatocellular; DNA Methylation; Epigenesis, Genetic; Genetic Variation; Genotype; Hepatitis B virus; Humans; Liver Neoplasms
PubMed: 32553521
DOI: 10.1016/j.clinre.2020.04.018 -
Journal of Chemical Theory and... Jan 2023The methylation of the lysine residue can affect some fundamental biological processes, and specific biological effects of the methylations are often related to product...
Structural and Energetic Origin of Different Product Specificities and Activities for SETD3 and Its Mutants on the Methylation of the β-Actin H73K Peptide: Insights from a QM/MM Study.
The methylation of the lysine residue can affect some fundamental biological processes, and specific biological effects of the methylations are often related to product specificity of methyltransferases. The question remains concerning how active-site structural features and dynamics control the activity as well as the number (1, 2, or 3) of methyl groups on methyl lysine products. SET domain containing protein 3 (SETD3) has been identified recently as the β-actin histidine73-N methyltransferase, and also, it has a weak methylation activity on the H73K β-actin peptide for which the target H73 residue is mutated into K73. Interestingly, the K73 methylation activity of SETD3 increases significantly as a result of the N255 → A or N255 → F/W273 → A mutation, and the N255A product specificity also differs from that of wild-type. Here, we performed QM/MM molecular dynamics and potential of mean force (PMF) simulations for SETD3 and its mutants (N255A and N255F/W273A) to study how SETD3 and its mutants could have different product specificities and activities for the K73 methylation. The PMF simulations show that the barrier for the first methylation of K73 is higher compared to the barrier of the H73 methylation in SETD3. Moreover, the second methylation of K73 has been found to have a barrier from the free energy simulation that is higher by 2.2 kcal/mol compared to the barrier of the first methyl transfer to K73, agreeing with the suggestion that SETD3 is a monomethylase. For the first, second, and third methylations of K73 in the N255A mutant, the barriers obtained from the PMF simulations for transferring the second and third methyl groups are found to be lower relative to the barrier for the first methyl transfer. Thus, N255A can be considered as a trimethyl lysine methyltransferase. In addition, for the first K73 methylation, the activities from the PMF simulations follow the order of N255F/W273A > N255A > WT, in agreement with experiments. The examination of the structural and dynamic results at the active sites provides better understanding of different product specificities and activities for the K73 methylations in SETD3 and its mutants. It is demonstrated that the existence of well-balanced interactions at the active site leading to the near attack conformation is of crucial importance for the efficient methyl transfers. Moreover, the presence of potential interactions (e.g., the C-H···O and cation-π interactions) that are strengthening at the transition state can also be important. Furthermore, the activity as well as product specificity of the K73 methylation also seems to be controlled by certain active-site water molecules which may be released to provide extra space for the addition of more methyl groups on K73.
Topics: Methylation; Histone-Lysine N-Methyltransferase; Actins; Lysine; Molecular Dynamics Simulation; Peptides
PubMed: 36520638
DOI: 10.1021/acs.jctc.2c00668 -
International Journal of Molecular... Feb 2024Lysine methylation is a major post-translational protein modification that occurs in both histones and non-histone proteins. Emerging studies show that the methylated... (Review)
Review
Lysine methylation is a major post-translational protein modification that occurs in both histones and non-histone proteins. Emerging studies show that the methylated lysine residues in non-histone proteins provide a proteolytic signal for ubiquitin-dependent proteolysis. The SET7 (SETD7) methyltransferase specifically transfers a methyl group from S-Adenosyl methionine to a specific lysine residue located in a methylation degron motif of a protein substrate to mark the methylated protein for ubiquitin-dependent proteolysis. LSD1 (Kdm1a) serves as a demethylase to dynamically remove the methyl group from the modified protein. The methylated lysine residue is specifically recognized by L3MBTL3, a methyl-lysine reader that contains the malignant brain tumor domain, to target the methylated proteins for proteolysis by the CRL4 ubiquitin ligase complex. The methylated lysine residues are also recognized by PHF20L1 to protect the methylated proteins from proteolysis. The lysine methylation-mediated proteolysis regulates embryonic development, maintains pluripotency and self-renewal of embryonic stem cells and other stem cells such as neural stem cells and hematopoietic stem cells, and controls other biological processes. Dysregulation of the lysine methylation-dependent proteolysis is associated with various diseases, including cancers. Characterization of lysine methylation should reveal novel insights into how development and related diseases are regulated.
Topics: Humans; Proteolysis; Lysine; Methylation; Protein Processing, Post-Translational; Histones; Brain Neoplasms; Ubiquitins; Histone-Lysine N-Methyltransferase; Chromosomal Proteins, Non-Histone
PubMed: 38396925
DOI: 10.3390/ijms25042248