Base-Pair Resolution DNA Methylation Sequencing Reveals Profoundly Divergent Epigenetic Landscapes in Acute Myeloid Leukemia
We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions.
Vyšlo v časopise:
Base-Pair Resolution DNA Methylation Sequencing Reveals Profoundly Divergent Epigenetic Landscapes in Acute Myeloid Leukemia. PLoS Genet 8(6): e32767. doi:10.1371/journal.pgen.1002781
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002781
Souhrn
We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions.
Zdroje
1. DohnerHEsteyEHAmadoriSAppelbaumFRBuchnerT 2010 Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115 453 474
2. AytonPMClearyML 2003 Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes & development 17 2298 2307
3. ArmstrongSAStauntonJESilvermanLBPietersRden BoerML 2002 MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genetics 30 41 47
4. ZeisigBBMilneTGarcia-CuellarMPSchreinerSMartinME 2004 Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Molecular and cellular biology 24 617 628
5. WardPSPatelJWiseDRAbdel-WahabOBennettBD 2010 The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer cell 17 225 234
6. XuWYangHLiuYYangYWangP 2011 Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of [alpha]-Ketoglutarate-Dependent Dioxygenases. Cancer Cell 19 17 30
7. LeshchenkoVVKuoPYShaknovichRYangDTGellenT 2010 Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 116 1025 1034
8. GuoJUSuYZhongCMingGLSongH 2011 Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell cycle 10 2662 2668
9. TahilianiMKohKPShenYPastorWABandukwalaH 2009 Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324 930 935
10. FigueroaMEAbdel-WahabOLuCWardPSPatelJ 2010 Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell 18 553 567
11. FigueroaMELugthartSLiYErpelinck-VerschuerenCDengX 2010 DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer cell 17 13 27
12. HansenKDTimpWBravoHCSabunciyanSLangmeadB 2011 Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43 768 775
13. IrizarryRALadd-AcostaCWenBWuZMontanoC 2009 The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature genetics 41 178 186
14. O'HaganHMWangWSenSDestefano ShieldsCLeeSS 2011 Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer cell 20 606 619
15. MeissnerAGnirkeABellGWRamsahoyeBLanderES 2005 Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic acids research 33 5868 5877
16. GuHBockCMikkelsenTSJagerNSmithZD 2010 Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution. Nature methods 7 133 136
17. BockCTomazouEMBrinkmanABMullerFSimmerF 2010 Quantitative comparison of genome-wide DNA methylation mapping technologies. Nature biotechnology 28 1106 1114
18. GuHSmithZDBockCBoylePGnirkeA 2011 Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling. Nature protocols 6 468 481
19. ListerRO'MalleyRCTonti-FilippiniJGregoryBDBerryCC 2008 Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133 523 536
20. AlvarezHOpalinskaJZhouLSohalDFazzariMJ 2011 Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis. PLoS Genet 7 e1001356 doi:10.1371/journal.pgen.1001356
21. FigueroaMESkrabanekLLiYJiemjitAFandyTE 2009 MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood 114 3448 3458
22. RheeIBachmanKEParkBHJairK-WYenR-WC 2002 DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416 552 556
23. JiHEhrlichLISeitaJMurakamiPDoiA 2010 Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467 338 342
24. KruegerFAndrewsSR 2011 Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics 27 1571 1572
25. BullingerLEhrichMDohnerKSchlenkRFDohnerH 2009 Quantitative DNA-methylation predicts survival in adult acute myeloid leukemia. Blood blood-2009-2003-211003
26. McLeanCYBristorDHillerMClarkeSLSchaarBT 2010 GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28 495 501
27. MokarramPKumarKBrimHNaghibalhossainiFSaberi-firooziM 2009 Distinct high-profile methylated genes in colorectal cancer. PLoS ONE 4 e7012 doi:10.1371/journal.pone.0007012
28. DhirMMontgomeryEAGlocknerSCSchuebelKEHookerCM 2008 Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 12 1745 1753
29. Roman-GomezJCordeuLAgirreXJimenez-VelascoASan Jose-EnerizE 2007 Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia. Blood 109 3462 3469
30. MoelansCBVerschuur-MaesAHvan DiestPJ 2011 Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. The Journal of pathology 225 222 231
31. WangZYuanXJiaoNZhuHZhangY 2011 CDH13 and FLBN3 Gene Methylation are Associated with Poor Prognosis in Colorectal Cancer. Pathology oncology research : POR
32. YamadaSNomotoSFujiiTTakedaSKanazumiN 2007 Frequent promoter methylation of M-cadherin in hepatocellular carcinoma is associated with poor prognosis. Anticancer research 27 2269 2274
33. YingJGaoZLiHSrivastavaGMurrayPG 2007 Frequent epigenetic silencing of protocadherin 10 by methylation in multiple haematologic malignancies. British journal of haematology 136 829 832
34. NarayanGFreddyAJXieDLiyanageHClarkL 2011 Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance. Genes, chromosomes & cancer 50 1043 1053
35. KuangSQTongWGYangHLinWLeeMK 2008 Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia 22 1529 1538
36. WeberMHellmannIStadlerMBRamosLPääboS 2007 Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genetics 39 457 466
37. KarolchikDKuhnRMBaertschRBarberGPClawsonH 2008 The UCSC Genome Browser Database: 2008 update. Nucleic Acids Res 36 D773 779
38. HeintzmanNDHonGCHawkinsRDKheradpourPStarkA 2009 Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459 108 112
39. HuangYSitwalaKBronsteinJSandersDDandekarM 2012 Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood 119 388 398
40. ValkPJVerhaakRGBeijenMAErpelinckCABarjesteh van Waalwijk van Doorn-KhosrovaniS 2004 Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350 1617 1628
41. WangQ-fWuGMiSHeFWuJ 2010 MLL fusion proteins preferentially regulate a subset of wild type MLL target genes in the leukemic genome. Blood
42. LuCWardPSKapoorGSRohleDTurcanS 2012 IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483 474 478
43. TrinhBNLongTINickelAEShibataDLairdPW 2002 DNA Methyltransferase Deficiency Modifies Cancer Susceptibility in Mice Lacking DNA Mismatch Repair. Molecular and Cellular Biology 22 2906 2917
44. EadsCANickelAELairdPW 2002 Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. Cancer research 62 1296 1299
45. BröskeA-MVockentanzLKharaziSHuskaMRManciniE 2009 DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nature Genetics 41 1207 1215
46. MaunakeaAKNagarajanRPBilenkyMBallingerTJD'SouzaC 2010 Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466 253 257
47. FernandezHFSunZYaoXLitzowMRLugerSM 2009 Anthracycline dose intensification in acute myeloid leukemia. The New England journal of medicine 361 1249 1259
48. EhrichMNelsonMRStanssensPZabeauMLiloglouT 2005 Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 102 15785 15790
49. FujitaPARheadBZweigASHinrichsASKarolchikD 2011 The UCSC Genome Browser database: update 2011. Nucleic acids research 39 D876 882
50. WangHQTuominenLKTsaiCJ 2011 SLIM: a sliding linear model for estimating the proportion of true null hypotheses in datasets with dependence structures. Bioinformatics 27 225 231
51. McLeanCYBristorDHillerMClarkeSLSchaarBT 2010 GREAT improves functional interpretation of cis-regulatory regions. Nature biotechnology 28 495 501
52. GiannopoulouEGElementoO 2011 An integrated ChIP-seq analysis platform with customizable workflows. BMC bioinformatics 12 277
53. KarolchikDHinrichsASFureyTSRoskinKMSugnetCW 2004 The UCSC Table Browser data retrieval tool. Nucleic acids research 32 D493 496
54. ErnstJKheradpourPMikkelsenTSShoreshNWardLD 2011 Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473 43 49
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 6
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