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Epigenetics Dec 2023African American (AA) men have the highest incidence and mortality rate from Prostate cancer (PCa) than any other racial/ethnic group. To date, PCa genomic studies have...
African American (AA) men have the highest incidence and mortality rate from Prostate cancer (PCa) than any other racial/ethnic group. To date, PCa genomic studies have largely under-represented tumour samples from AA men. We measured genome-wide DNA methylation in benign and tumor prostate tissues from AA men using the Illumina Infunium 850 K EPIC array. mRNA expression database from a subset of the AA biospecimen were used to assess correlation of transcriptome and methylation datasets. Genome-wide methylation analysis identified 11,460 probes that were significant (p < 0.01) and differentially methylated in AA PCa compared to normal prostate tissues and showed significant (p < 0.01) inverse-correlation with mRNA expression. Ingenuity pathway analysis and Gene Ontology analysis in our AA dataset compared with TCGA dataset showed similarities in methylation patterns: top candidate genes with significant hypermethylation and corresponding down-regulated gene expression were associated with biological pathways in hemidesmosome assembly, mammary gland development, epidermis development, hormone biosynthesis, and cell communication. In addition, top candidate genes with significant hypomethylation and corresponding up-regulated gene expression were associated with biological pathways in macrophage differentiation, cAMP-dependent protein kinase activity, protein destabilization, transcription co-repression, and fatty acid biosynthesis. In contrast, differences in genome-wide methylation in our AA dataset compared with TCGA dataset were enriched for genes in steroid signalling, immune signalling, chromatin structure remodelling and RNA processing. Overall, differential methylation of 3, 3, 1, 7, 2C, 2, 2, 292, 2, 1, and 6 were significant and uniquely associated with PCa progression in our AA cohort.
Topics: Male; Humans; DNA Methylation; Transcriptome; Black or African American; Epigenomics; Prostatic Neoplasms; RNA, Messenger; Gene Expression Regulation, Neoplastic; CpG Islands; Carrier Proteins; Nerve Tissue Proteins
PubMed: 37279148
DOI: 10.1080/15592294.2023.2180585 -
The Journal of Organic Chemistry Jun 2021The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of...
The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of enaminones with further diastereoselective and functional groups tolerant hydrogenation to α-methylketones are developed. The scope and limitations of the proposed methodology are discussed. The advantages compared to known procedures are demonstrated. The unexpected role of acetone in the hydrogenation is suggested. The evaluation of the method for both early building block synthesis and late-stage CH-functionalization is shown. The elaborate procedures' preparability and scalability are demonstrated by the synthesis of several α-methyl ketones up to 100 g amount.
Topics: Catalysis; Hydrogenation; Ketones; Methylation
PubMed: 34042433
DOI: 10.1021/acs.joc.1c00148 -
Progress in Molecular Biology and... 2023The epigenome consists of all the epigenetic alterations like DNA methylation, the histone modifications and non-coding RNAs which change the gene expression and have a...
The epigenome consists of all the epigenetic alterations like DNA methylation, the histone modifications and non-coding RNAs which change the gene expression and have a role in diseases like cancer and other processes. Epigenetic modifications can control gene expression through variable gene activity at various levels which affects various cellular phenomenon such as cell differentiations, variability, morphogenesis, and the adaptability of an organism. Various factors such as food, pollutants, drugs, stress etc., impact the epigenome. Epigenetic mechanisms mainly involve various post-translational alteration of histones and DNA methylation. Numerous methods have been utilized to study these epigenetic marks. Various histone modifications and binding of histone modifier proteins can be analyzed using chromatin immunoprecipitation (ChIP) which is one of broadly utilized method. Other modified forms of the ChIP have been developed such as reverse chromatin immunoprecipitation (R-ChIP); sequential ChIP (ChIP-re-ChIP) and some high-throughput modified forms of ChIP such as ChIP-seq and ChIP-on-chip. Another epigenetic mechanism is DNA methylation, in which DNA methyltransferases (DNMTs) add a methyl group to the C-5 position of the cytosine. Bisulfite sequencing is the oldest and usually utilized method to measure the DNA methylation status. Other techniques have been established are whole genome bisulfite sequencing (WGBS), methylated DNA immune-precipitation based methods (MeDIP), methylation sensitive restriction enzyme digestion followed by sequencing (MRE-seq) and methylation BeadChip to study the methylome. This chapter briefly discusses the key principles and methods used to study epigenetics in health and disease conditions.
Topics: Humans; Epigenesis, Genetic; DNA Methylation; Sulfites; Histones; DNA
PubMed: 37019594
DOI: 10.1016/bs.pmbts.2023.02.004 -
Organic Letters Sep 2021Methyl groups can imbue valuable properties in organic molecules, often leading to enhanced bioactivity. To enable efficient installation of methyl groups on simple...
Methyl groups can imbue valuable properties in organic molecules, often leading to enhanced bioactivity. To enable efficient installation of methyl groups on simple building blocks and in late-stage functionalization, a nickel-catalyzed reductive coupling of secondary Katritzky alkylpyridinium salts with methyl iodide was developed. When coupled with formation of the pyridinium salt from an alkyl amine, this method allows amino groups to be readily transformed to methyl groups with broad functional group and heterocycle tolerance.
Topics: Amines; Catalysis; Methylation; Molecular Structure; Nickel; Pyridinium Compounds
PubMed: 34464140
DOI: 10.1021/acs.orglett.1c02458 -
Journal of Biological Rhythms Jun 2022Methylation, that is, the transfer or synthesis of a -CH group onto a target molecule, is a pervasive biochemical modification found in organisms from bacteria to...
Methylation, that is, the transfer or synthesis of a -CH group onto a target molecule, is a pervasive biochemical modification found in organisms from bacteria to humans. In mammals, a complex metabolic pathway powered by the essential nutrients vitamin B9 and B12, methionine and choline, synthesizes -adenosylmethionine, the methyl donor in the methylation of nucleic acids, proteins, fatty acids, and small molecules by over 200 substrate-specific methyltransferases described so far in humans. Methylations not only play a key role in scenarios for the origin and evolution of life, but they remain essential for the development and physiology of organisms alive today, and methylation deficiencies contribute to the etiology of many pathologies. The methylation of histones and DNA is important for circadian rhythms in many organisms, and global inhibition of methyl metabolism similarly affects biological rhythms in prokaryotes and eukaryotes. These observations, together with various pieces of evidence scattered in the literature on circadian gene expression and metabolism, indicate a close mutual interdependence between biological rhythms and methyl metabolism that may originate from prebiotic chemistry. This perspective first proposes an abiogenetic scenario for rhythmic methylations and then outlines mammalian methyl metabolism, before reanalyzing previously published data to draw a tentative map of its profound connections with the circadian clock.
Topics: Animals; Circadian Rhythm; Folic Acid; Humans; Mammals; Methionine; Methylation; S-Adenosylmethionine
PubMed: 35382619
DOI: 10.1177/07487304221083507 -
Cancer Research Communications Feb 2022The difference in cancer morbidity and mortality between individuals of different racial groups is complex. Health disparities provide a framework to explore potential...
The difference in cancer morbidity and mortality between individuals of different racial groups is complex. Health disparities provide a framework to explore potential connections between poor outcomes and individuals of different racial backgrounds. This study identifies genomic changes in African-American patients with gynecologic malignancies, a population with well-established disparities in outcomes. Our data explore whether social health disparities might mediate interactions between the environment and tumor epigenomes and genomes that can be identified. Using The Cancer Genetic Ancestry Atlas, which encodes data from The Cancer Genome Atlas by ancestry and allows for systematic analyses of sequencing data by racial group, we performed large-scale, comparative analyses to identify novel targets with alterations in methylation, transcript, and microRNA expression between tumors from women of European American or African American racial groups across all gynecologic malignancies. We identify novel discrete genomic changes in these complex malignancies and suggest a framework for identifying novel therapeutic targets for future investigation.
Topics: Humans; Female; Genital Neoplasms, Female; Racial Groups; Black or African American; Genomics; White
PubMed: 35992327
DOI: 10.1158/2767-9764.crc-21-0018 -
Environment International Aug 2023Native American communities suffer disproportionately from elevated metal exposures and increased risk for cardiovascular diseases and diabetes. DNA methylation is a...
INTRODUCTION
Native American communities suffer disproportionately from elevated metal exposures and increased risk for cardiovascular diseases and diabetes. DNA methylation is a sensitive biomarker of aging-related processes and novel epigenetic-based "clocks" can be used to estimate accelerated biological aging that may underlie increased risk. Metals alter DNA methylation, yet little is known about their individual and combined impact on epigenetic age acceleration. Our objective was to investigate the associations of metals on several DNA methylation-based aging measures in the Strong Heart Study (SHS) cohort.
METHODS
Blood DNA methylation data from 2,301 SHS participants was used to calculate age acceleration of epigenetic clocks (PhenoAge, GrimAge, DunedinPACE, Hannum, Horvath). Urinary metals [arsenic (As), cadmium (Cd), tungsten (W), zinc (Zn), selenium (Se), molybdenum (Mo)] were creatinine-adjusted and categorized into quartiles. We examined associations of individual metals through linear regression models and used Bayesian Kernel Machine Regression (BKMR) for the impact of the total metal mixture on epigenetic age acceleration.
RESULTS
The mixture of nonessential metals (W, As, Cd) was associated with greater GrimAge acceleration and DunedinPACE, while the essential metal mixture (Se, Zn, Mo) was associated with lower epigenetic age acceleration. Cd was associated with increased epigenetic age acceleration across all clocks and BKMR analysis suggested nonlinear associations between Se and DunedinPACE, GrimAge, and PhenoAge acceleration. No interactions between individual metals were observed. The associations between Cd, Zn, and epigenetic age acceleration were greater in never smokers in comparison to current/former smokers.
CONCLUSION
Nonessential metals were positively associated with greater epigenetic age acceleration, with strongest associations observed between Cd and DunedinPACE and GrimAge acceleration. In contrast, essential metals were associated with lower epigenetic aging. Examining the influence of metal mixtures on epigenetic age acceleration can provide insight into metals and aging-related diseases.
Topics: Humans; Aging; American Indian or Alaska Native; Arsenic; Bayes Theorem; Cadmium; DNA Methylation; Epigenesis, Genetic; Metals; Selenium; Zinc
PubMed: 37364305
DOI: 10.1016/j.envint.2023.108064 -
International Journal of Biological... Dec 2023RNA methylation, an epigenetic modification that does not alter gene sequence, may be important to diverse biological processes. Protein regulators of RNA methylation... (Review)
Review
RNA methylation, an epigenetic modification that does not alter gene sequence, may be important to diverse biological processes. Protein regulators of RNA methylation include "writers," "erasers," and "readers," which respectively deposit, remove, and recognize methylated RNA. RNA methylation, particularly N6-methyladenosine (m6A), 5-methylcytosine (m5C), N3-methylcytosine (m3C), N1-methyladenosine (m1A) and N7-methylguanosine (m7G), has been suggested as disease therapeutic targets. Despite advances in the structure and pharmacology of RNA methylation regulators that have improved drug discovery, regulating these proteins by various post-translational modifications (PTMs) has received little attention. PTM modifies protein structure and function, affecting all aspects of normal biology and pathogenesis, including immunology, cell differentiation, DNA damage repair, and tumors. It is becoming evident that RNA methylation regulators are also regulated by diverse PTMs. PTM of RNA methylation regulators induces their covalent linkage to new functional groups, hence modifying their activity and function. Mass spectrometry has identified many PTMs on protein regulators of RNA methylation. In this review, we describe the functions and PTM of protein regulators of RNA methylation and summarize the recent advances in the regulatory mode of human disease and its underlying mechanisms.
Topics: Humans; Methylation; RNA; Epigenesis, Genetic; Protein Processing, Post-Translational; Cell Differentiation
PubMed: 37690652
DOI: 10.1016/j.ijbiomac.2023.126773 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Nov 2023Methylation plays a vital role in biological systems. SAM (-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation... (Review)
Review
Methylation plays a vital role in biological systems. SAM (-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation reactions. SAM-dependent methyltransferases (MTase) transfer a methyl group from SAM to substrates, thereby altering their physicochemical properties or biological activities. In recent years, many SAM analogues with alternative methyl substituents have been synthesized and applied to methyltransferases that specifically transfer different groups to the substrates. These include functional groups for labeling experiments and novel alkyl modifications. This review summarizes the recent progress in the synthesis and application of SAM methyl analogues and prospects for future research directions in this field.
Topics: S-Adenosylmethionine; Methionine; Methyltransferases; Methylation; Racemethionine
PubMed: 38013176
DOI: 10.13345/j.cjb.230271 -
Medical Oncology (Northwood, London,... Jan 2023DNA methylation is one among the major grounds of cancer progression which is characterized by the addition of a methyl group to the promoter region of the gene thereby... (Review)
Review
DNA methylation is one among the major grounds of cancer progression which is characterized by the addition of a methyl group to the promoter region of the gene thereby causing gene silencing or increasing the probability of mutations; however, in bacteria, methylation is used as a defense mechanism where DNA protection is by addition of methyl groups making restriction enzymes unable to cleave. Hypermethylation and hypomethylation both pose as leading causes of oncogenesis; the former being more frequent which occurs at the CpG islands present in the promoter region of the genes, whereas the latter occurs globally in various genomic sequences. Reviewing methylation profiles would help in the detection and treatment of cancers. Demethylation is defined as preventing methyl group addition to the cytosine DNA base which could cause cancers in case of global hypomethylation, however, upon further investigation; it could be used as a therapeutic tool as well as for drug design in cancer treatment. In this review, we have studied the molecules that induce and enzymes (DNMTs) that bring about methylation as well as comprehend the correlation between methylation with transcription factors and various signaling pathways. DNA methylation has also been reviewed in terms of how it could serve as a prognostic marker and the various therapeutic drugs that have come into the market for reversing methylation opening an avenue toward curing cancers.
Topics: Humans; DNA Methylation; Prognosis; Neoplasms; Gene Expression Regulation; Gene Silencing; CpG Islands; Gene Expression Regulation, Neoplastic; DNA (Cytosine-5-)-Methyltransferases
PubMed: 36602616
DOI: 10.1007/s12032-022-01943-1