Dnmt3a Protects Active Chromosome Domains against Cancer-Associated Hypomethylation

English version České info

Changes in genomic DNA methylation patterns are generally assumed to play an important role in the etiology of human cancers. The Dnmt3a enzyme is required for the establishment of normal methylation patterns, and mutations in Dnmt3a have been described in leukemias. Deletion of Dnmt3a in a K-ras–dependent mouse lung cancer model has been shown to promote tumor progression, which suggested that the enzyme might suppress tumor development by stabilizing DNA methylation patterns. We have used whole-genome bisulfite sequencing to comprehensively characterize the methylomes from Dnmt3a wildtype and Dnmt3a-deficient mouse lung tumors. Our results show that profound global methylation changes can occur in K-ras–induced lung cancer. Dnmt3a wild-type tumors were characterized by large hypomethylated domains that correspond to nuclear lamina-associated domains. In contrast, Dnmt3a-deficient tumors showed a uniformly hypomethylated genome. Further data analysis revealed that Dnmt3a is required for efficient maintenance methylation of active chromosome domains and that Dnmt3a-deficient tumors show moderate levels of gene deregulation in these domains. In summary, our results uncover conserved features of cancer methylomes and define the role of Dnmt3a in maintaining DNA methylation patterns in cancer.

Vyšlo v časopise: Dnmt3a Protects Active Chromosome Domains against Cancer-Associated Hypomethylation. PLoS Genet 8(12): e32767. doi:10.1371/journal.pgen.1003146
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003146

Souhrn

Zdroje

1. JonesPA, BaylinSB (2007) The epigenomics of cancer. Cell 128: 683–692.

2. EhrlichM (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21: 5400–5413.

3. FeinbergAP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447: 433–440.

4. EstellerM (2008) Epigenetics in cancer. N Engl J Med 358: 1148–1159.

5. HansenKD, TimpW, BravoHC, SabunciyanS, LangmeadB, et al. (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43: 768–775.

6. BermanBP, WeisenbergerDJ, AmanJF, HinoueT, RamjanZ, et al. (2012) Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 44: 40–46.

7. GollMG, BestorTH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74: 481–514.

8. LairdPW, Jackson-GrusbyL, FazeliA, DickinsonSL, JungWE, et al. (1995) Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81: 197–205.

9. LinH, YamadaY, NguyenS, LinhartH, Jackson-GrusbyL, et al. (2006) Suppression of intestinal neoplasia by deletion of Dnmt3b. Mol Cell Biol 26: 2976–2983.

10. LinhartHG, LinH, YamadaY, MoranE, SteineEJ, et al. (2007) Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 21: 3110–3122.

11. SteineEJ, EhrichM, BellGW, RajA, ReddyS, et al. (2011) Genes methylated by DNA methyltransferase 3b are similar in mouse intestine and human colon cancer. J Clin Invest 121: 1748–1752.

12. OkanoM, BellDW, HaberDA, LiE (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257.

13. LeyTJ, DingL, WalterMJ, McLellanMD, LamprechtT, et al. (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363: 2424–2433.

14. YanXJ, XuJ, GuZH, PanCM, LuG, et al. (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43: 309–315.

15. WalterMJ, DingL, ShenD, ShaoJ, GrillotM, et al. (2011) Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25: 1153–1158.

16. CouronneL, BastardC, BernardOA (2012) TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med 366: 95–96.

17. ChallenGA, SunD, JeongM, LuoM, JelinekJ, et al. (2012) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44: 23–31.

18. GaoQ, SteineEJ, BarrasaMI, HockemeyerD, PawlakM, et al. (2011) Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression. Proc Natl Acad Sci U S A 108: 18061–18066.

19. TuvesonDA, ShawAT, WillisNA, SilverDP, JacksonEL, et al. (2004) Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5: 375–387.

20. ListerR, O'MalleyRC, Tonti-FilippiniJ, GregoryBD, BerryCC, et al. (2008) Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133: 523–536.

21. ListerR, PelizzolaM, DowenRH, HawkinsRD, HonG, et al. (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462: 315–322.

22. RamsahoyeBH, BiniszkiewiczD, LykoF, ClarkV, BirdAP, et al. (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci USA 97: 5237–5242.

23. GuelenL, PagieL, BrassetE, MeulemanW, FazaMB, et al. (2008) Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453: 948–951.

24. Peric-HupkesD, MeulemanW, PagieL, BruggemanSW, SoloveiI, et al. (2010) Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell 38: 603–613.

25. HeintzmanND, HonGC, HawkinsRD, KheradpourP, StarkA, et al. (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459: 108–112.

26. ListerR, PelizzolaM, KidaYS, HawkinsRD, NeryJR, et al. (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471: 68–73.

27. HonGC, HawkinsRD, CaballeroOL, LoC, ListerR, et al. (2012) Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res 22: 246–258.

28. LiangG, ChanMF, TomigaharaY, TsaiYC, GonzalesFA, et al. (2002) Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 22: 480–491.

29. ChenT, UedaY, DodgeJE, WangZ, LiE (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23: 5594–5605.

30. SharmaS, De CarvalhoDD, JeongS, JonesPA, LiangG (2011) Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance. PLoS Genet 7: e1001286 doi:10.1371/journal.pgen.1001286.

31. JonesPA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13: 484–492.

32. LaurentL, WongE, LiG, HuynhT, TsirigosA, et al. (2010) Dynamic changes in the human methylome during differentiation. Genome Res 20: 320–331.

33. ShuklaS, KavakE, GregoryM, ImashimizuM, ShutinoskiB, et al. (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479: 74–79.

34. LykoF, ForetS, KucharskiR, WolfS, FalckenhaynC, et al. (2010) The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol 8: e1000506 doi:10.1371/journal.pbio.1000506.

35. XiY, LiW (2009) BSMAP: whole genome bisulfite sequence MAPping program. BMC Bioinformatics 10: 232.

36. ShenY, et al. (2012) A map of cis-regulatory sequences in the mouse genome. Nature 488: 116–120.

37. OoiAT, RamS, KuoA, GilbertJL, YanW, et al. (2012) Identification of an interleukin 13-induced epigenetic signature in allergic airway inflammation. Am J Transl Res 4: 219–228.

38. HuangDW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.