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Cited by 660Epigenetics and DNA MethylationGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina–associated domains

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Berman, Benjamin P, Weisenberger, Daniel J, Aman, Joseph F, Hinoue, Toshinori, Ramjan, Zachary, Liu, Yaping, Noushmehr, Houtan, Lange, Christopher P E +4 more·2012·Nature Genetics
DOI 10.1038/ng.969PMC PMC4309644
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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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  • PMDs in HCC are enriched with repressive histone modifications and associated with transcriptional repression.

    “These domains were enriched with repressive histone modifications and associated with transcriptional repression (Supplementary Fig. 2c, d)44–46.”

    From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [46]

    The Main section (Fig. 5d; page unavailable) reports enrichment of the repressive H3K9me3 mark within IMR-90 fibroblast PMDs. It also reports reduced expression of two genes within colorectal-tumor PMDs (Fig. 5a–b). These findings support parts of the general association, but the paper does not establish the stated histone and transcriptional findings for PMDs in HCC. (LLM, conf=0.88)

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Research works printed but not linked: 33

  1. [1]Jones PA Baylin SB The fundamental role of epigenetic events in cancer Nat. Rev. Genet 2002 3 415 428 12042769
  2. [2]Gal-Yam EN Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line Proc. Natl. Acad. Sci. USA 2008 105 12979 12984 18753622 PMC2529074
  3. [3]Irizarry RA The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores Nat. Genet 2009 41 178 186 19151715 PMC2729128
  4. [4]Gebhard C General transcription factor binding at CpG islands in normal cells correlates with resistance to de novo DNA methylation in cancer cells Cancer Res 2010 70 1398 1407 20145141
  5. [5]Noushmehr H Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma Cancer Cell 2010 17 510 522 20399149 PMC2872684
  6. [6]Hinoue T Genome-scale analysis of aberrant DNA methylation in colorectal cancer Genome Res 2011 6 9 published online, PMC3266034 21659424
  7. [7]Lister R Human DNA methylomes at base resolution show widespread epigenomic differences Nature 2009 462 315 322 19829295 PMC2857523
  8. [8]Lister R Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells Nature 2011 471 68 73 21289626 PMC3100360
  9. [9]ENCODE Project Consortium User's guide to the encyclopedia of DNA elements (ENCODE) PLoS Biol 2011 9 e1001046 21526222 PMC3079585
  10. [10]Irizarry RA Wu H Feinberg AP A species-generalized probabilistic model-based definition of CpG islands Mamm. Genome 2009 20 674 680 19777308 PMC2962567
  11. [11]Widschwendter M Epigenetic stem cell signature in cancer Nat. Genet 2007 39 157 158 17200673
  12. [14]Visel A ChIP-seq accurately predicts tissue-specific activity of enhancers Nature 2009 457 854 858 19212405 PMC2745234
  13. [16]Boumber YA An Sp1/Sp3 binding polymorphism confers methylation protection PLoS Genet 2008 4 e1000162 18725933 PMC2515197
  14. [18]Estécio MR Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer Genome Res 2010 20 1369 1382 20716667 PMC2945186
  15. [19]Heinz S Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities Mol. Cell 2010 38 576 589 20513432 PMC2898526
  16. [20]Aguilera C c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex Nature 2011 469 231 235 21196933
  17. [21]Jones PA The DNA methylation paradox Trends Genet 1999 15 34 37 10087932
  18. [22]Hellman A Chess A Gene body-specific methylation on the active X chromosome Science 2007 315 1141 1143 17322062
  19. [23]Frigola J Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band Nat. Genet 2006 38 540 549 16642018
  20. [24]Coolen MW Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity Nat. Cell Biol 2010 12 235 246 20173741 PMC3058354
  21. [25]Guelen L Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions Nature 2008 453 948 951 18463634
  22. [26]Peric-Hupkes D Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation Mol. Cell 2010 38 603 613 20513434 PMC5975946
  23. [27]Chua YL 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 4041 4052 19802002 PMC2789334
  24. [28]Dahl E Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma Oncogene 2007 26 5680 5691 17353908
  25. [29]Witcher M Emerson BM Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary Mol. Cell 2009 34 271 284 19450526 PMC2723750
  26. [30]Hawkins RD Distinct epigenomic landscapes of pluripotent and lineage-committed human cells Cell Stem Cell 2010 6 479 491 20452322 PMC2867844
  27. [32]Hansen RS Sequencing newly replicated DNA reveals widespread plasticity in human replication timing Proc. Natl. Acad. Sci. USA 2010 107 139 144 19966280 PMC2806781
  28. [33]Aran D Toperoff G Rosenberg M Hellman A Replication timing-related and gene body-specific methylation of active human genes Hum. Mol. Genet 2011 20 670 680 21112978
  29. [34]Lieberman-Aiden E Comprehensive mapping of long-range interactions reveals folding principles of the human genome Science 2009 326 289 293 19815776 PMC2858594
  30. [35]Pickersgill H Characterization of the Drosophila melanogaster genome at the nuclear lamina Nat. Genet 2006 38 1005 1014 16878134
  31. [36]Xiang Y JMJD3 is a histone H3K27 demethylase Cell Res 2007 17 850 857 17923864
  32. [38]Sun W Integrated study of copy number states and genotype calls using high-density SNP arrays Nucleic Acids Res 2009 37 5365 5377 19581427 PMC2935461
  33. [39]Balwierz PJ Methods for analyzing deep sequencing expression data: constructing the human and mouse promoterome with deepCAGE data Genome Biol 2009 10 R79 19624849 PMC2728533

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Authors
Berman, B. P., Weisenberger, D. J., Aman, J. F., Hinoue, T., Ramjan, Z., Liu, Y., Noushmehr, H., Lange, C. P. E., van Dijk, C. M., Tollenaar, R. A. E. M., Van Den Berg, D., & Laird, P. W.
Affiliations
  • University of Southern California (US)
  • Leiden University Medical Center (NL)
Corresponding author
Laird, Peter W
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2011-11-27
Volume
44
Issue
1
Pages
40-46
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.969
PMC
PMC4309644
OpenAlex
W1984562049
Cited by
660
References
6
Citations by year
2026: 15 · 2025: 25 · 2024: 26 · 2023: 29 · 2022: 39 · 2021: 46 · 2020: 38 · 2019: 36 · 2018: 51 · 2017: 67 · 2016: 54 · 2015: 75 · 2014: 63 · 2013: 58 · 2012: 35
FWCI
20.54
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
Funders
National Cancer Institute (R01CA118699, P30CA014089)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
DNA methylation, colorectal cancer, nuclear lamina, lamina-associated domains, CpG islands, 3D genome organization, tumor suppressor gene silencing, whole-genome bisulfite sequencing
MeSH terms
Adenocarcinoma, Colon, DNA, Neoplasm, Humans, Colorectal Neoplasms, Genome, Human, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Gene Silencing, Nuclear Lamina, Cell Line, Tumor

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