DNA methylation: a historical perspective

Trends in Genetics, Journal Year: 2022, Volume and Issue: 38(7), P. 676 - 707

Published: April 30, 2022

5mC was discovered in mammals and found to have a nonrandom distribution that suggested possible biological function.In the early 1980s, DNA methylation within 5′ promoter regions, but not elsewhere, inhibit transcription of associated gene.Throughout 1990s 2000s, mechanisms gene regulation by were elucidated as well its relationship with histone modifications influence on 3D genome organization uncovered.Over past decade, high-throughput sequencing technologies complemented earlier single-gene efforts ultimately provided global understanding dynamics development disease. In 1925, 5-methylcytosine first reported bacteria. However, importance intuitive for several decades. After this initial lag, ubiquitous presence methylated base emerged across all domains life revealed range essential functions. Today, we are armed knowledge key factors establish, maintain, remove access staggering rapidly growing number base-resolution maps. Despite this, fundamental details about precise role interpretation patterns remain under investigation. Here, review field from beginning present day, an emphasis findings mammalian systems, point reader select experiments form foundation field. A quarter century ago, one pioneers methylation, Rudolf Jaenisch, outlined August 1997 issue Trends Genetics why should bother caring speculated which developmental contexts it might function [1.Jaenisch R. imprinting: bother?.Trends Genet. 1997; 13: 323-329Abstract Full Text PDF PubMed Scopus (313) Google Scholar]. would like still bother, what learned nearly research, need address coming years. Since discovery bacteria has been investigated vast organisms is linked topics organization, reproduction development, disease aging. It most well-studied epigenetic mechanism often used classical example inheritance, although recent advances shown modification be more dynamic, hence complex, than previously thought [2.Ginno P.A. et al.A genome-scale map turnover identifies site-specific dependencies DNMT TET activity.Nat. Commun. 2020; 11: 2680Crossref (45) Scholar, 3.Charlton J. al.TETs compete DNMT3 activity pluripotent cells at thousands somatic enhancers.Nat. 52: 819-827Crossref (34) 4.Spada F. al.Active genomic methylcytosine cells.Nat. Chem. Biol. 16: 1411-1419Google ever-growing body work published each year, remains difficult pinpoint genome. also unresolved differentiated, pluripotent, [5.Jackson-Grusby L. al.Loss causes p53-dependent apoptosis deregulation.Nat. 2001; 27: 31-39Crossref (558) 6.Chen T. al.Establishment maintenance mouse embryonic stem Dnmt3a Dnmt3b.Mol. Cell. 2003; 23: 5594-5605Crossref (560) 7.Tsumura A. al.Maintenance self-renewal ability absence methyltransferases Dnmt1, Dnmt3b.Genes Cells. 2006; 805-814Crossref (394) Scholar] altered into distinct landscape cancer types [8.Baylin S.B. Jones Epigenetic determinants cancer.Cold Spring Harb. Perspect. 2016; 8a019505Crossref (468) As typical articles design focus summarizing discoveries around their time [9.Jones Laird P.W. Cancer epigenetics comes age.Nat. 1999; 21: 163-167Crossref (2028) 10.Bird memory.Genes Dev. 2002; 6-21Crossref (5200) 11.Suzuki M.M. Bird landscapes: provocative insights epigenomics.Nat. Rev. 2008; 9: 465-476Crossref (2109) 12.Jones Liang G. Rethinking how maintained.Nat. 2009; 10: 805-811Crossref (537) 13.Law J.A. Jacobsen S.E. Establishing, maintaining modifying plants animals.Nat. 2010; 204-220Crossref (2344) 14.Smith Z.D. Meissner methylation: roles development.Nat. 2013; 14: (1783) 15.Du al.DNA pathways crosstalk methylation.Nat. Mol. Cell 2015; 519-532Crossref (494) 16.Lyko The methyltransferase family: versatile toolkit regulation.Nat. 2018; 19: 81-92Crossref (486) 17.Greenberg M.V.C. Bourc'his, D. diverse disease.Nat. 2019; 20: 590-607Crossref (533) 18.Parry during cell fate decisions.Nat. 2021; 22: 59-66Crossref (37) Scholar], decided complement providing systematic covering entire history highlight many foundational our current built. expected, primary literature vast, apologize having omit elegant summarize emergence progression century. At turn 20th century, Walter Sutton (1902) Theodore Boveri (1903) independently proposed chromosomal theory linking Gregor Mendel's (1866) long overlooked laws behavior inheritance own meiosis [19.Sutton W.S. On morphology chromosome group Brachystola magna.Biol. Bull. 1902; 4: 24-39Crossref Scholar,20.Sutton chromosomes heredity.Biol. 1903; 231-251Crossref This initially controversial gained credence following 1910 paper detractors, Thomas Hunt Morgan, who demonstrated eye color Drosophila melanogaster determined X chromosome, decisive piece evidence support [21.Morgan T.H. Sex limited Drosophila.Science. 1910; 32: 120-122Crossref Levene Jacobs' research nucleic acids they reside polymer chain nucleotides [22.Levene Jacobs W.A. Über die hefe-nucleinsäure.Ber. Dtsch. Ges. 1909; 42: 2474-2478Crossref (0) interest composition these laid among others epigenetics, central actor (Figure 1A ). Johnson Coghill isolated crystalized Mycobacterium tuberculosis effort identify pathogenic determinant. One candidates (5mC) (see Glossary), nucleotide had postulated occur naturally living based his previous success vitro biochemical synthesis [23.Wheeler H.L. Researches pyrimidine derivatives.J. Am. Soc. 1904; 31: 591-606Google Microscopic examination hydrolyzed acid picrate crystals polarized light indeed distinguished cytosine [24.Johnson T.B. R.D. pyrimidines. C111. 5-methyl-cytosine tuberculinic acid, tubercle bacillus.J. 1925; 47: 2838-2844Crossref seemingly relevant discovery, next report only 23 years later. Using chromatography [25.Vischer E. Chargaff separation characterization purines minute amounts hydrolysates.J. 1947; 168: 781Abstract Hotchkiss observed faint band near chromatograph calf thymus behaved cytosine, yet slightly shifted migration, leading him suggest some therefore labeled 'epi-cytosine' [26.Hotchkiss quantitative purines, pyrimidines, nucleosides chromatography.J. 1948; 175: 315-332Abstract 1B). Specifically, he noted epi-cytosine relates terms absorption spectrum mobility same manner thymine uracil. 5-methyluracil, inferred could possibly 5mC. Two later, Wyatt confirmed mammalian, insect, plant broad quantities [27.Wyatt G.R. Occurrence acids.Nature. 1950; 166: 237-238Crossref Scholar,28.Wyatt Recognition estimation acids.Biochem. 1951; 48: 581-584Crossref carriers genetic information [29.Avery O.T. al.Studies chemical nature substance inducing transformation pneumococcal types.J. Exp. Med. 1944; 79: 137-158Crossref Scholar,30.Hershey B.A.D. Chase M. Independent functions viral protein growth bacteriophage.J. Gen. Physiol. 1952; 36: 39-56Crossref structure double helix [31.Watson J.D. Crick F.H.C. Molecular acids: deoxyribose acid.Nature. 1953; 171: 737-738Crossref (7945) grew. Sinsheimer subsequently randomly distributed specifically CpG dinucleotide context 1C). Interestingly, doublet frequently expected eukaryotic [32.Smith Markham Polynucleotides deoxyribonucleic 170: 120-121Crossref Scholar,33.Sinsheimer R.L. al.The action pancreatic desoxyribonuclease. I. Isolation mono- dinucleotides.J. 1954; 208: 445-459Abstract Why did take so before started progress rapidly? obvious reason historical discovery. know chains carry information. 1928 Frederick Griffith [34.Griffith significance Hyg. 1928; 113-159Crossref 1944 Avery-MacLeod-McCarty experiment conclusion Second World War, 1952 Hershey-Chase [30.Hershey resolution helped lay needed enabled exploration relevance DNA. additional may caused hesitation: other groups find isolates Scholar,35.Vischer Ernst al.Microbial desoxypentose avian bacilli yeast.J. 1949; 177: 429-438Abstract low abundance seemed disqualifying major function. aside, worth mentioning parallel experimental advances, biologist Conrad Waddington coined term 'epigenetics' 1942 [36.Waddington C.H. epigenotype.Endeavour. 1942; 1: 18-20Crossref widely 1957 [37.Waddington Strategy Genes; Discussion Some Aspects Theoretical Biology. Allen & Unwin, 1957Google Scholar]; however, concepts until became clearer over subsequent dawn molecular biology set stage thorough investigation appreciation mammals. made studying [38.Borek Srinivasan P.R. acids.Annu. Biochem. 1966; 35: 275-298Crossref tractable abundant model organism, prokaryotes thereby paved way study higher 2A Luria, Bertani, Weigle different families bacteriophage diverge infect certain bacterial strains [39.Luria Mutations viruses affecting host range.Genetics. 1945; 30: 84-99PubMed Scholar,40.Bertani J.J. Host controlled variation viruses.J. Bacteriol. 65: 113-121Crossref basis strain specificity infection due phage's differential enter strains, rather because once inside, incompatible phage degraded immune-like response [41.Lederberg S. Suppression multiplication heterologous bacteriophages lysogenic bacteria.Virology. 1957; 3: 496-513Google mechanistic advance strain-specific activity, raised possibility defense against phages [42.Gold enzymatic RNA DNA, II. species enzymes.Proc. Natl. Acad. Sci. U. 1963; 50: 164-169Crossref Thus, Arber restriction system (R-M system) where methylation-sensitive 'restriction enzymes' defend invading digesting Bacterial protected enzymes species-specific [43.Arber W. Host-controlled bacteriophage.Annu. Microbiol. 1965; 365-378Crossref Beyond protection, link between replication [44.Billen Hewitt Influence starvation methionine amino replication.J. 92: 609-617Google Billen normal Escherichia coli growth, evident behind fork exclusively placed unmethylated nascent strand 2B). methionine, methyl donor, led strand, retained get after S phase when added back media [45.Billen Methylation chromosome: event "replication point"?.J. 1968; 477-486Crossref cannot serve template round [46.Lark C. Studies vivo 15T.J. 389-399Crossref deficient methyl-donor showed degradation [47.Lark produced coli.J. 1970; 337-348Crossref 1964 modifications, Borek plays defining bacteria, similar act eukaryotes underlie type diversity [48.Srinivasan Enzymatic alteration structure: put finishing touches characteristic insertion groups.Science. 1964; 145: 548-553Crossref Four nuclear extracts tissues adult rat tested methylate various species. extracts, such kidney or liver, harbor potent brain spleen extracts. Based observations, organism content [49.Sheid B. al.Deoxyribonucleic methylase tissues.Biochemistry. 7: 280-285Crossref gleaned studies basics immunity replication, though remained unclear whether any conserved organisms. responsible adding cytosines polymers. regulated, thus path specific target modification. particular, tissue-specific rodents intriguing, data too sparse draw meaningful conclusions yet. Once clear 5mC, despite relatively abundance, does play general regulatory credibility. fields, important technological enable informative theoretical models decade. plants, indicated widespread modification, further using mass spectrometry. 1970s, Vanyushin quantified levels animals, including sponges, mollusks, sea urchins, bony fish, amphibians, reptiles, [50.Vanyushin B.F. al.Rare bases animal DNA.Nature. 225: 948-949Crossref (290) Scholar,51.Vanyushin DNA: tissue specificity.Biochim. Biophys. Acta. 1973; 299: 397-403Crossref These analyses while both GC can differ species, closely related generally comparable tissues. later sequence varying [52.Guseinov V.A. Content localisation healthy wilt-infected cotton plants.Biochim. Acta (BBA) - Nucleic Acids Protein Synth. 1975; 395: 229-238Google reports profiling spectrometry accumulated, organisms, that: (i) no [53.Adams R.L.P. fibroblasts.Biochim. 1971; 254: 205-212Crossref Scholar,54.Adams Delayed developing urchin embryos.Nat. New 244: 27-29Crossref (ii) guide mutations, required transcriptional changes [55.Scarano control differentiation embryogenesis.Adv. Cytopharmacolo. 13-24PubMed (iii) activator [56.Comings D.E. euchromatic heterochromatic DNA.Exp. Res. 1972; 74: 383-390Crossref (Box 1). 1975, three notable reviews unique frameworks contemplating investigating effects [57.Holliday Pugh J.E. development.Science. 187: 226-232Crossref (1302) 58.Riggs A.D. inactivation, differentiation, methylation.Cytogenet. 9-25Crossref 59.Sager Kitchin Selective silencing DNA.Science. 189: 426-433Crossref While differed specific, rationalized mechanisms, fundamentally agreed regulating expression orchestrating development.Box 1Early theories methylationWork prior 1970s scientists propose formal hypotheses eukaryotes. late 1960s, Scarano colleagues 90% CG them speculate [277.Scarano heterogeneity origin isostichs embryos.Proc. 1967; 57: 1394-1400Crossref Scholar,278.Grippo P. al.Methylation embryos.J. 195-208Crossref 1971, spontaneous deamination generates C→T conversion, lead heritable sequence. popular 1960s up 1980s mutations genes direct differentiation. 5mC-guided mutation cellular embryogenesis Scholar].In Adams' patterning fibroblasts replicating quickly, takes hours become fully methylated. observation active occurs predominantly S-phase Adams conclude must controlling His influenced Lark implicated regulator Scholar,46.Lark 1972 Comings came looking Chinese hamster ovarian cells, AT-rich undermethylated greater extent composition, GC-rich highly if high transcription, then CG→TA actively selected euchromatin To Comings, idea enriched regions activator.In 1973, twice pluteus morula [54.Adams agreement suggesting urchins gastrulation [278.Grippo Scholar,279.Comb D.G. embryo development.J. 851-855Crossref quantify stage, revise regulate instead new 'switch off' contributing development. Work

Language: Английский

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Therapeutic potential of pyrrole and pyrrolidine analogs: an update

Molecular Diversity, Journal Year: 2022, Volume and Issue: 26(5), P. 2915 - 2937

Published: Jan. 25, 2022

Language: Английский

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Regulation, functions and transmission of bivalent chromatin during mammalian development

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(1), P. 6 - 26

Published: Aug. 26, 2022

Language: Английский

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Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(1), P. 18 - 29

Published: Jan. 1, 2022

Language: Английский

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TET (Ten-eleven translocation) family proteins: structure, biological functions and applications

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 11, 2023

Abstract Ten-eleven translocation (TET) family proteins (TETs), specifically, TET1, TET2 and TET3, can modify DNA by oxidizing 5-methylcytosine (5mC) iteratively to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxycytosine (5caC), then two of these intermediates (5fC 5caC) be excised return unmethylated cytosines thymine-DNA glycosylase (TDG)-mediated base excision repair. Because methylation demethylation play an important role in numerous biological processes, including zygote formation, embryogenesis, spatial learning immune homeostasis, the regulation TETs functions is complicated, dysregulation their implicated many diseases such as myeloid malignancies. In addition, recent studies have demonstrated that able catalyze hydroxymethylation RNA perform post-transcriptional regulation. Notably, catalytic-independent certain contexts been identified, further highlighting multifunctional roles. Interestingly, reactivating expression selected target genes, accumulated evidences support potential therapeutic use TETs-based editing tools disorders associated with epigenetic silencing. this review, we summarize key findings functions, activity regulators at various levels, technological advances detection 5hmC, main oxidative product, emerging applications editing. Furthermore, discuss existing challenges future directions field.

Language: Английский

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Epigenetic Regulation of Cellular Senescence

Cells, Journal Year: 2022, Volume and Issue: 11(4), P. 672 - 672

Published: Feb. 15, 2022

Senescence is a complex cellular stress response that abolishes proliferative capacity and generates unique secretory pattern implicated in organismal aging age-related disease. How cell transitions to senescent state multifactorial often requires transcriptional regulation of multiple genes. Epigenetic alterations DNA chromatin are powerful regulators genome architecture gene expression, they play crucial role mediating the induction maintenance senescence. This review will highlight changes chromatin, methylation, histone establish maintain senescence, alongside specific epigenetic senescence-associated phenotype (SASP).

Language: Английский

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Single-molecule footprinting identifies context-dependent regulation of enhancers by DNA methylation

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(5), P. 787 - 802.e9

Published: Feb. 8, 2023

Enhancers are cis-regulatory elements that control the establishment of cell identities during development. In mammals, enhancer activation is tightly coupled with DNA demethylation. However, whether this epigenetic remodeling necessary for unknown. Here, we adapted single-molecule footprinting to measure chromatin accessibility and transcription factor binding as a function presence methylation on same molecules. We leveraged natural heterogeneity at active enhancers test impact their in multiple lineages. Although reduction appears dispensable activity most enhancers, identify class cell-type-specific where antagonizes factors. Genetic perturbations reveal require demethylation these loci. Thus, addition safeguarding genome from spurious activation, directly controls occupancy enhancers.

Language: Английский

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Epigenetics-targeted drugs: current paradigms and future challenges

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

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Orthologous Mammalian A3A-Mediated Single-Nucleotide Resolution Sequencing of DNA Epigenetic Modification 5-Hydroxymethylcytosine

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Epigenetic modifications in genomes play a crucial role regulating gene expression mammals. Among these modifications, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are recognized as the fifth sixth nucleobases genomes, respectively, two most significant epigenetic marks 5hmC serves both an intermediate active DNA demethylation stable modification involved various biological processes. Analyzing location of is essential for understanding its functions. In this study, we introduce orthologous mammalian A3A-mediated sequencing (OMA-seq) method quantitative detection genomic at single-nucleotide resolution. OMA-seq relies on deamination properties naturally occurring A3A proteins: green monkey (gmA3A) dog (dogA3A). The combined use gmA3A dogA3A effectively deaminates cytosine (C) 5mC, but not 5hmC. As result, original C 5mC deaminated read thymine (T) during sequencing, while remains unchanged C. Consequently, remaining sequence indicates presence Using OMA-seq, successfully quantified from lung cancer tissue corresponding normal tissue. enables accurate mapping resolution, utilizing pioneering single-step protocol that leverages high specificity natural deaminases. This approach eliminates need bisulfite conversion, glycosylation, chemical oxidation, or screening engineered protein variants, thereby streamlining analysis utilization enzymes expands toolkit research, enabling precise modified nucleosides uncovering new insights into regulation.

Language: Английский

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LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer

Cell Research, Journal Year: 2025, Volume and Issue: 35(1), P. 59 - 71

Published: Jan. 2, 2025

Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity therapy response. In castration-resistant prostate (CRPC), intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading a scarcity effective clinical treatments. Utilizing single-cell RNA sequencing on both human mouse samples, combined with whole-genome bisulfite multiple genetically engineered models, we investigated molecular mechanism AR-independent uncovered potential therapeutic strategy. Single-cell transcriptomic profiling cancers, pre- post-androgen deprivation therapy, revealed an association liver kinase B1 (LKB1) pathway inactivation AR independence. LKB1 led global DNA hypomethylation during progression. Importantly, pharmacological inhibition TET enzymes supplementation S-adenosyl methionine were found effectively suppress growth. These insights shed light driving propose strategy targeting in CRPC.

Language: Английский

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