Regions of Focal DNA Hypermethylation and Long-range Hypomethylation in Colorectal Cancer Coincide with Nuclear Lamina-associated Domains

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Nov 29

PMID 22120008

Citations 357

Authors

Benjamin P Berman

Daniel J Weisenberger

Joseph F Aman

Toshinori Hinoue

Zachary Ramjan

Yaping Liu

Houtan Noushmehr

Christopher P E Lange

Cornelis M van Dijk

Rob A E M Tollenaar

David van den Berg

Peter W Laird

Affiliations

Soon will be listed here.

Abstract

Extensive changes in DNA methylation are common in cancer and may contribute to oncogenesis through transcriptional silencing of tumor-suppressor genes. Genome-scale studies have yielded important insights into these changes but have focused on CpG islands or gene promoters. We used whole-genome bisulfite sequencing (bisulfite-seq) to comprehensively profile a primary human colorectal tumor and adjacent normal colon tissue at single-basepair resolution. Regions of focal hypermethylation in the tumor were located primarily at CpG islands and were concentrated within regions of long-range (>100 kb) hypomethylation. These hypomethylated domains covered nearly half of the genome and coincided with late replication and attachment to the nuclear lamina in human cell lines. We confirmed the confluence of hypermethylation and hypomethylation within these domains in 25 diverse colorectal tumors and matched adjacent tissue. We propose that widespread DNA methylation changes in cancer are linked to silencing programs orchestrated by the three-dimensional organization of chromatin within the nucleus.

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References

Balwierz P, Carninci P, Daub C, Kawai J, Hayashizaki Y, van Belle W . Methods for analyzing deep sequencing expression data: constructing the human and mouse promoterome with deepCAGE data. Genome Biol. 2009; 10(7):R79. PMC: 2728533. DOI: 10.1186/gb-2009-10-7-r79. View

Jones P . The DNA methylation paradox. Trends Genet. 1999; 15(1):34-7. DOI: 10.1016/s0168-9525(98)01636-9. View

Ohm J, McGarvey K, Yu X, Cheng L, Schuebel K, Cope L . A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007; 39(2):237-42. PMC: 2744394. DOI: 10.1038/ng1972. View

Dahl E, Wiesmann F, Woenckhaus M, Stoehr R, Wild P, Veeck J . Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene. 2007; 26(38):5680-91. DOI: 10.1038/sj.onc.1210345. View

Pickersgill H, Kalverda B, de Wit E, Talhout W, Fornerod M, van Steensel B . Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat Genet. 2006; 38(9):1005-14. DOI: 10.1038/ng1852. View

Hellman A, Chess A . Gene body-specific methylation on the active X chromosome. Science. 2007; 315(5815):1141-3. DOI: 10.1126/science.1136352. View

Nili Gal-Yam E, Egger G, Iniguez L, Holster H, Einarsson S, Zhang X . Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc Natl Acad Sci U S A. 2008; 105(35):12979-84. PMC: 2529074. DOI: 10.1073/pnas.0806437105. View

Chua Y, Ito Y, Pole J, Newman S, Chin S, Stein R . The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Oncogene. 2009; 28(46):4041-52. PMC: 2789334. DOI: 10.1038/onc.2009.259. View

Hawkins R, Hon G, Lee L, Ngo Q, Lister R, Pelizzola M . Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 2010; 6(5):479-91. PMC: 2867844. DOI: 10.1016/j.stem.2010.03.018. View

10.

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

11.

Aran D, Toperoff G, Rosenberg M, Hellman A . Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet. 2010; 20(4):670-80. DOI: 10.1093/hmg/ddq513. View

12.

Lieberman-Aiden E, van Berkum N, Williams L, Imakaev M, Ragoczy T, Telling A . Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009; 326(5950):289-93. PMC: 2858594. DOI: 10.1126/science.1181369. View

13.

Noushmehr H, Weisenberger D, Diefes K, Phillips H, Pujara K, Berman B . Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010; 17(5):510-22. PMC: 2872684. DOI: 10.1016/j.ccr.2010.03.017. View

14.

Witcher M, Emerson B . Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell. 2009; 34(3):271-84. PMC: 2723750. DOI: 10.1016/j.molcel.2009.04.001. View

15.

Irizarry R, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P . The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009; 41(2):178-186. PMC: 2729128. DOI: 10.1038/ng.298. View

16.

Coolen M, Stirzaker C, Song J, Statham A, Kassir Z, Moreno C . Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat Cell Biol. 2010; 12(3):235-46. PMC: 3058354. DOI: 10.1038/ncb2023. View

17.

Guelen L, Pagie L, Brasset E, Meuleman W, Faza M, Talhout W . Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008; 453(7197):948-51. DOI: 10.1038/nature06947. View

18.

Hinoue T, Weisenberger D, Lange C, Shen H, Byun H, van den Berg D . Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2011; 22(2):271-82. PMC: 3266034. DOI: 10.1101/gr.117523.110. View

19.

Sun W, Wright F, Tang Z, Nordgard S, Van Loo P, Yu T . Integrated study of copy number states and genotype calls using high-density SNP arrays. Nucleic Acids Res. 2009; 37(16):5365-77. PMC: 2935461. DOI: 10.1093/nar/gkp493. View

20.

Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J . Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007; 39(2):232-6. DOI: 10.1038/ng1950. View