#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Odborné časopisy / PLOS Genetics / 2015 - 2

An Integrative Multi-scale Analysis of the Dynamic DNA Methylation Landscape in Aging

English version České info

Two well-known features of aging are the gradual decline of the body’s ability to regenerate tissues, as well as an increased incidence of diseases like cancer and Alzheimers. One of the most recent exciting findings which may underlie the aging process is a gradual modification of DNA, called epigenetic drift, which is effected by the covalent addition and removal of methyl groups, which in turn can deregulate the activity of nearby genes. However, this study presents the most convincing evidence to date that epigenetic drift acts to stabilize the activity levels of nearby genes. This study shows that instead, epigenetic drift may act primarly to disrupt DNA binding patterns of proteins which regulate the activity of many genes, and moreover identifies specific regulatory proteins with key roles in cancer and Alzheimers. The study also performs the most comprehensive analysis of epigenetic drift at different spatial scales, demonstrating that epigenetic drift on the largest length scales is highly reminiscent of those seen in cancer. In summary, this work substantially supports the view that epigenetic drift may contribute to the age-associated increased risk of diseases like cancer and Alzheimers, by disrupting master regulators of genomewide gene activity.

Vyšlo v časopise: An Integrative Multi-scale Analysis of the Dynamic DNA Methylation Landscape in Aging. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004996
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004996

Souhrn

Two well-known features of aging are the gradual decline of the body’s ability to regenerate tissues, as well as an increased incidence of diseases like cancer and Alzheimers. One of the most recent exciting findings which may underlie the aging process is a gradual modification of DNA, called epigenetic drift, which is effected by the covalent addition and removal of methyl groups, which in turn can deregulate the activity of nearby genes. However, this study presents the most convincing evidence to date that epigenetic drift acts to stabilize the activity levels of nearby genes. This study shows that instead, epigenetic drift may act primarly to disrupt DNA binding patterns of proteins which regulate the activity of many genes, and moreover identifies specific regulatory proteins with key roles in cancer and Alzheimers. The study also performs the most comprehensive analysis of epigenetic drift at different spatial scales, demonstrating that epigenetic drift on the largest length scales is highly reminiscent of those seen in cancer. In summary, this work substantially supports the view that epigenetic drift may contribute to the age-associated increased risk of diseases like cancer and Alzheimers, by disrupting master regulators of genomewide gene activity.

Zdroje

1. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, et al. (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20 : 332–340. doi: 10.1101/gr.096826.109 20107151

2. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, et al. (2010) Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 20 : 440–446. doi: 10.1101/gr.103606.109 20219944

3. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, et al. (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20 : 434–439. doi: 10.1101/gr.103101.109 20219945

4. Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, et al. (2012) Distinct DNA methylomes of newborns and centenarians. Proceedings of the National Academy of Sciences.

5. Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, et al. (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49 : 359–67. doi: 10.1016/j.molcel.2012.10.016 23177740

6. Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14: R115. doi: 10.1186/gb-2013-14-10-r115 24138928

7. Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, et al. (2013) Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12 : 413–25. doi: 10.1016/j.stem.2013.01.017 23415915

8. Teschendorff AE, Jones A, Fiegl H, Sargent A, Zhuang JJ, et al. (2012) Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med 4 : 24. doi: 10.1186/gm323 22453031

9. Teschendorff AE, West J, Beck S (2013) Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Hum Mol Genet 22: R7–R15. doi: 10.1093/hmg/ddt375 23918660

10. West J, Widschwendter M, Teschendorff AE (2013) Distinctive topology of age-associated epigenetic drift in the human interactome. Proc Natl Acad Sci U S A 110 : 14138–43. doi: 10.1073/pnas.1307242110 23940324

11. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, et al. (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol 31 : 142–7. doi: 10.1038/nbt.2487 23334450

12. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Gayther SA, et al. (2009) An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One 4: e8274. doi: 10.1371/journal.pone.0008274 20019873

13. Langevin SM, Houseman EA, Accomando WP, Koestler DC, Christensen BC, et al. (2014) Leukocyte-adjusted epigenome-wide association studies of blood from solid tumor patients. Epigenetics 9 : 884–95. doi: 10.4161/epi.28575 24671036

14. Jaffe AE, Irizarry RA (2014) Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol 15: R31. doi: 10.1186/gb-2014-15-2-r31 24495553

15. Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, et al. (2012) DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 13 : 86. doi: 10.1186/1471-2105-13-86 22568884

16. Houseman EA, Molitor J, Marsit CJ (2014) Reference-free cell mixture adjustments in analysis of DNA methylation data. Bioinformatics 30 : 1431–9. doi: 10.1093/bioinformatics/btu029 24451622

17. Berman BP, Weisenberger DJ, Aman JF, Hinoue T, Ramjan Z, et al. (2012) Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 44 : 40–6. doi: 10.1038/ng.969

18. Timp W, Bravo HC, McDonald OG, Goggins M, Umbricht C, et al. (2014) Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors. Genome Med 6 : 61. doi: 10.1186/s13073-014-0061-y 25191524

19. Ziller MJ, Gu H, Muller F, Donaghey J, Tsai LT, et al. (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500 : 477–81. doi: 10.1038/nature12433 23925113

20. Beck S (2010) Taking the measure of the methylome. Nat Biotechnol 28 : 1026–8. doi: 10.1038/nbt1010-1026 20944589

21. Hovestadt V, Jones DT, Picelli S, Wang W, Kool M, et al. (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510 : 537–41. doi: 10.1038/nature13268 24847876

22. Essaghir A, Toffalini F, Knoops L, Kallin A, van Helden J, et al. (2010) Transcription factor regulation can be accurately predicted from the presence of target gene signatures in microarray gene expression data. Nucleic Acids Res 38: e120. doi: 10.1093/nar/gkq149 20215436

23. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489 : 57–74. doi: 10.1038/nature11247

24. Gerstein MB, Kundaje A, Hariharan M, Landt SG, Yan KK, et al. (2012) Architecture of the human regulatory network derived from encode data. Nature 489 : 91–100. doi: 10.1038/nature11245 22955619

25. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, et al. (2012) The accessible chromatin landscape of the human genome. Nature 489 : 75–82. doi: 10.1038/nature11232 22955617

26. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, et al. (2014) Minfi: a flexible and comprehensive bioconductor package for the analysis of infinium DNA methylation microarrays. Bioinformatics 30 : 1363–9. doi: 10.1093/bioinformatics/btu049 24478339

27. Jaffe AE, Feinberg AP, Irizarry RA, Leek JT (2012) Significance analysis and statistical dissection of variably methylated regions. Biostatistics 13 : 166–78. doi: 10.1093/biostatistics/kxr013 21685414

28. Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, et al. (2012) Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol 13: R97. doi: 10.1186/gb-2012-13-10-r97 23034122

29. Jones A, Teschendorff AE, Li Q, Hayward JD, Kannan A, et al. (2013) Role of DNA methylation and epigenetic silencing of hand2 in endometrial cancer development. PLoS Med 10: e1001551. doi: 10.1371/journal.pmed.1001551 24265601

30. Network CGA (2012) Comprehensive molecular portraits of human breast tumours. Nature 490 : 61–70. doi: 10.1038/nature11412

31. Nejman D, Straussman R, Steinfeld I, Ruvolo M, Roberts D, et al. (2014) Molecular rules governing de novo methylation in cancer. Cancer Res 74 : 1475–83. doi: 10.1158/0008-5472.CAN-13-3042 24453003

32. Steegenga WT, Boekschoten MV, Lute C, Hooiveld GJ, de Groot PJ, et al. (2014) Genome-wide age-related changes in DNA methylation and gene expression in human pbmcs. Age (Dordr) 36 : 9648. doi: 10.1007/s11357-014-9648-x

33. de Jong S, Neeleman M, Luykx JJ, ten Berg MJ, Strengman E, et al. (2014) Seasonal changes in gene expression represent cell-type composition in whole blood. Hum Mol Genet 23 : 2721–8. doi: 10.1093/hmg/ddt665 24399446

34. Jiao Y, Widschwendter M, Teschendorff AE (2014) A systems-level integrative framework for genome-wide DNA methylation and gene expression data identifies differential gene expression modules under epigenetic control. Bioinformatics 30 : 2360–6. doi: 10.1093/bioinformatics/btu316 24794928

35. Votavova H, M MMD, Fejglova K, Vasikova A, Krejcik Z, et al. (2011) Transcriptome alterations in maternal and fetal cells induced by tobacco smoke. Placenta 32 : 763–770. doi: 10.1016/j.placenta.2011.06.022 21803418

36. Beineke P, Fitch K, Tao H, Elashoff MR, Rosenberg S, et al. (2012) A whole blood gene expression-based signature for smoking status. BMC Med Genomics 5 : 58. doi: 10.1186/1755-8794-5-58 23210427

37. Nazor KL, Altun G, Lynch C, Tran H, Harness JV, et al. (2012) Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell 10 : 620–34. doi: 10.1016/j.stem.2012.02.013 22560082

38. Lee CS, Friedman JR, Fulmer JT, Kaestner KH (2005) The initiation of liver development is dependent on foxa transcription factors. Nature 435 : 944–7. doi: 10.1038/nature03649 15959514

39. Cereghini S (1996) Liver-enriched transcription factors and hepatocyte differentiation. FASEB J 10 : 267–82. 8641560

40. Lu T, Aron L, Zullo J, Pan Y, Kim H, et al. (2014) Rest and stress resistance in ageing and alzheimer’s disease. Nature 507 : 448–54. doi: 10.1038/nature13163 24670762

41. Day K, Waite LL, Thalacker-Mercer A, West A, Bamman MM, et al. (2013) Differential DNA methylation with age displays both common and dynamic features. Genome Biol 14: R102. doi: 10.1186/gb-2013-14-9-r102 24034465

42. Alisch RS, Barwick BG, Chopra P, Myrick LK, Satten GA, et al. (2012) Age-associated DNA methylation in pediatric populations. Genome Res 22 : 623–32. doi: 10.1101/gr.125187.111 22300631

43. Martino D, Loke YJ, Gordon L, Ollikainen M, Cruickshank MN, et al. (2013) Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 14: R42. doi: 10.1186/gb-2013-14-5-r42 23697701

44. Glass D, Vinuela A, Davies MN, Ramasamy A, Parts L, et al. (2013) Gene expression changes with age in skin, adipose tissue, blood and brain. Genome Biol 14: R75. doi: 10.1186/gb-2013-14-7-r75 23889843

45. Huehne R, Thalheim T, Suehnel J (2014) Agefactdb–the jenage ageing factor database–towards data integration in ageing research. Nucleic Acids Res 42: D892–6. doi: 10.1093/nar/gkt1073

46. Walter D, Matter A, Fahrenkrog B (2014) Loss of histone h3 methylation at lysine 4 triggers apoptosis in saccharomyces cerevisiae. PLoS Genet 10: e1004095. doi: 10.1371/journal.pgen.1004095 24497836

47. Lui JC, Chen W, Cheung CS, Baron J (2014) Broad shifts in gene expression during early postnatal life are associated with shifts in histone methylation patterns. PLoS One 9: e86957. doi: 10.1371/journal.pone.0086957 24489814

48. Tacutu R, Craig T, Budovsky A, Wuttke D, Lehmann G, et al. (2013) Human ageing genomic resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res 41: D1027–33. doi: 10.1093/nar/gks1155 23193293

49. Ayer DE (1999) Histone deacetylases: transcriptional repression with siners and nurds. Trends Cell Biol 9 : 193–8. doi: 10.1016/S0962-8924(99)01536-6 10322454

50. Nascimento EM, Cox CL, MacArthur S, Hussain S, Trotter M, et al. (2011) The opposing transcriptional functions of sin3a and c-myc are required to maintain tissue homeostasis. Nat Cell Biol 13 : 1395–405. doi: 10.1038/ncb2385 22101514

51. Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, et al. (2013) A beta-mixture quantile normalization method for correcting probe design bias in illumina infinium 450 k DNA methylation data. Bioinformatics 29 : 189–96. doi: 10.1093/bioinformatics/bts680 23175756

52. Troyanskaya O, Cantor M, Sherlock G, Brown P, Hastie T, et al. (2001) Missing value estimation methods for DNA microarrays. Bioinformatics 17 : 520–525. doi: 10.1093/bioinformatics/17.6.520 11395428

53. Teschendorff AE, Zhuang J, Widschwendter M (2011) Independent surrogate variable analysis to deconvolve confounding factors in large-scale microarray profiling studies. Bioinformatics 27 : 1496–1505. doi: 10.1093/bioinformatics/btr171 21471010

Štítky
Genetika Reprodukčná medicína
Článek 2014 Reviewer Thank You
Článek Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for and Myocardial Infarction
Článek African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania
Článek Genomics of Divergence along a Continuum of Parapatric Population Differentiation
Článek microRNAs Regulate Cell-to-Cell Variability of Endogenous Target Gene Expression in Developing Mouse Thymocytes
Článek A Rolling Circle Replication Mechanism Produces Multimeric Lariats of Mitochondrial DNA in
Článek Closing the Gap between Knowledge and Clinical Application: Challenges for Genomic Translation
Článek Partially Redundant Enhancers Cooperatively Maintain Mammalian Expression Above a Critical Functional Threshold
Článek Discovery of Transcription Factors and Regulatory Regions Driving Tumor Development by ATAC-seq and FAIRE-seq Open Chromatin Profiling
Článek Mutations in Result in Ocular Coloboma, Microcornea and Cataracts
Článek A Genome-Wide Hybrid Incompatibility Landscape between and
Článek Recurrent Evolution of Melanism in South American Felids
Článek Discovery of CTCF-Sensitive Cis-Spliced Fusion RNAs between Adjacent Genes in Human Prostate Cells
Článek Tissue Expression Pattern of PMK-2 p38 MAPK Is Established by the miR-58 Family in
Článek Essential Role for Endogenous siRNAs during Meiosis in Mouse Oocytes
Článek Matrix Metalloproteinase 2 Is Required for Ovulation and Corpus Luteum Formation in
Článek Evolutionary Signatures amongst Disease Genes Permit Novel Methods for Gene Prioritization and Construction of Informative Gene-Based Networks
Článek RR-1 Cuticular Protein TcCPR4 Is Required for Formation of Pore Canals in Rigid Cuticle
Článek GC-Content Evolution in Bacterial Genomes: The Biased Gene Conversion Hypothesis Expands
Článek Proteotoxic Stress Induces Phosphorylation of p62/SQSTM1 by ULK1 to Regulate Selective Autophagic Clearance of Protein Aggregates
Článek K-homology Nuclear Ribonucleoproteins Regulate Floral Organ Identity and Determinacy in Arabidopsis
Článek A Nitric Oxide Regulated Small RNA Controls Expression of Genes Involved in Redox Homeostasis in
Článek HYPER RECOMBINATION1 of the THO/TREX Complex Plays a Role in Controlling Transcription of the Gene in Arabidopsis
Článek Mitochondrial and Cytoplasmic ROS Have Opposing Effects on Lifespan
Článek Structured Observations Reveal Slow HIV-1 CTL Escape
Článek Combining Natural Sequence Variation with High Throughput Mutational Data to Reveal Protein Interaction Sites
Článek Transhydrogenase Promotes the Robustness and Evolvability of Deficient in NADPH Production
Článek Regulators of Autophagosome Formation in Muscles
Článek Genomic Selection and Association Mapping in Rice (): Effect of Trait Genetic Architecture, Training Population Composition, Marker Number and Statistical Model on Accuracy of Rice Genomic Selection in Elite, Tropical Rice Breeding Lines
Článek Eye Selector Logic for a Coordinated Cell Cycle Exit
Článek Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations
Článek The DNA Polymerase δ Has a Role in the Deposition of Transcriptionally Active Epigenetic Marks, Development and Flowering
Článek Contribution of the Two Genes Encoding Histone Variant H3.3 to Viability and Fertility in Mice
Článek Membrane Recognition and Dynamics of the RNA Degradosome
Článek P-TEFb, the Super Elongation Complex and Mediator Regulate a Subset of Non-paused Genes during Early Embryo Development
Článek is a Long Non-coding RNA in JNK Signaling in Epithelial Shape Changes during Drosophila Dorsal Closure
Článek A Pleiotropy-Informed Bayesian False Discovery Rate Adapted to a Shared Control Design Finds New Disease Associations From GWAS Summary Statistics
Článek Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers
Článek and Hyperdrive Mechanisms (in Mouse Meiosis)
Článek Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells
Článek Systemic Delivery of MicroRNA-101 Potently Inhibits Hepatocellular Carcinoma by Repressing Multiple Targets
Článek Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in and Implicates Other Immune Related Genes
Článek Abscission Is Regulated by the ESCRT-III Protein Shrub in Germline Stem Cells
Článek Temperature Stress Mediates Decanalization and Dominance of Gene Expression in
Článek Transcriptome Wide Annotation of Eukaryotic RNase III Reactivity and Degradation Signals
Článek The Exosome Component Rrp6 Is Required for RNA Polymerase II Termination at Specific Targets of the Nrd1-Nab3 Pathway
Článek Sex-specific -regulatory Variation on the X Chromosome
Článek Regulation of Toll-like Receptor Signaling by the SF3a mRNA Splicing Complex
Článek Modeling of the Human Alveolar Rhabdomyosarcoma Chromosome Translocation in Mouse Myoblasts Using CRISPR-Cas9 Nuclease
Článek Asymmetry of the Budding Yeast Tem1 GTPase at Spindle Poles Is Required for Spindle Positioning But Not for Mitotic Exit
Článek TIM Binds Importin α1, and Acts as an Adapter to Transport PER to the Nucleus
Článek Antagonistic Roles for KNOX1 and KNOX2 Genes in Patterning the Land Plant Body Plan Following an Ancient Gene Duplication
Článek The Genetic Architecture of the Genome-Wide Transcriptional Response to ER Stress in the Mouse
Článek Fatty Acid Synthase Cooperates with Glyoxalase 1 to Protect against Sugar Toxicity
Článek Region-Specific Activation of mRNA Translation by Inhibition of Bruno-Mediated Repression
Článek An Essential Role of the Arginine Vasotocin System in Mate-Guarding Behaviors in Triadic Relationships of Medaka Fish ()
Článek Interaction between the tRNA-Binding and C-Terminal Domains of Yeast Gcn2 Regulates Kinase Activity In Vivo
Článek Hyper-Acetylation of Histone H3K56 Limits Break-Induced Replication by Inhibiting Extensive Repair Synthesis
Článek Prodomain Removal Enables Neto to Stabilize Glutamate Receptors at the Neuromuscular Junction
Článek Recent Selective Sweeps in North American Show Signatures of Soft Sweeps
Článek Identification and Functional Analysis of Healing Regulators in
Článek A Multi-Megabase Copy Number Gain Causes Maternal Transmission Ratio Distortion on Mouse Chromosome 2
Článek Drosophila Casein Kinase I Alpha Regulates Homolog Pairing and Genome Organization by Modulating Condensin II Subunit Cap-H2 Levels
Článek The Hippo Pathway Regulates Homeostatic Growth of Stem Cell Niche Precursors in the Ovary
Článok vyšiel v časopise

PLOS Genetics

2015 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

nový kurz
Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#