The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing
Open accessAbstract
Adult cancers may derive from stem or early progenitor cells. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“hypermethylated regions (HyperDMRs) in HCC were enriched in the promoters of developmental genes and in genic features such as untranslated regions (UTRs) and exons (Fig. 1b and Supplementary Fig. 2f)47,48.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [47]
In the citing paper
“Inhibitors of DNMT, LSD1 and EZH2 can derepress endogenous retroviral elements (ERVs) leading to activation of endogenous anti-viral RNA sensing pathways and tumour type I interferon production, which acts in an autocrine manner to drive expression of interferon stimulated genes (ISGs) 191-193,226 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [226]
Citations
Cites
Prospective identification of tumorigenic breast cancer cells
Al‐Hajj, M., Wicha, M. S., Benito‐Hernández, A., Morrison, S. J., & Clarke, M. F. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0530291100 · Cited by 10,579
The fundamental role of epigenetic events in cancer
Jones, P. A., & Baylin, S. B. (2002) · Nature Reviews Genetics · doi:10.1038/nrg816 · Cited by 5,648
Self-citationMethylation-specific PCR: a novel PCR assay for methylation status of CpG islands.
Herman, J. G., Graff, J. R., Myöhänen, S., Nelkin, B. D., & Baylin, S. B. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.18.9821 · Cited by 5,634
Self-citationA bivalent chromatin structure marks key developmental genes in embryonic stem cells
Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.041 · Cited by 5,361
Polycomb complexes repress developmental regulators in murine embryonic stem cells
Boyer, L. A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L. A., Lee, T. I., Levine, S. S., Wernig, M., Tajonar, A., Ray, M. K., et al. (2006) · Nature · doi:10.1038/nature04733 · Cited by 2,568
The history of cancer epigenetics
Feinberg, A. P., & Tycko, B. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1279 · Cited by 2,404
Cancer-epigenetics comes of age
Jones, P. A., & Laird, P. W. (1999) · Nature Genetics · doi:10.1038/5947 · Cited by 2,358
Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells
Lee, T. I., Jenner, R. G., Boyer, L. A., Guenther, M. G., Levine, S. S., Kumar, R., Chevalier, B. S., Johnstone, S. E., Cole, M. F., Isono, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.043 · Cited by 2,296
The Polycomb group protein EZH2 directly controls DNA methylation
Viré, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., et al. (2006) · Nature · doi:10.1038/nature04431 · Cited by 2,204
Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction?
Baylin, S. B., & Ohm, J. E. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1799 · Cited by 1,657
Self-citationChromatin signatures of pluripotent cell lines
Azuara, V., Perry, P., Sauer, S., Spivakov, M., Jørgensen, H. F., John, R. M., Gouti, M., Casanova, M., Warnes, G., Merkenschlager, M., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1403 · Cited by 1,357
Polycomb silencers control cell fate, development and cancer
Sparmann, A., & van Lohuizen, M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1991 · Cited by 1,339
Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitionsPreprint
Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H., & Helin, K. (2006) · Genes & Development · doi:10.1101/gad.381706 · Cited by 1,286
Tissue repair and stem cell renewal in carcinogenesis
Beachy, P. A., Karhadkar, S. S., & Berman, D. M. (2004) · Nature · doi:10.1038/nature03100 · Cited by 1,210
Self-citationEpigenetic Regulation of Cellular Memory by the Polycomb and Trithorax Group Proteins
Ringrose, L., & Paro, R. (2004) · Annual Review of Genetics · doi:10.1146/annurev.genet.38.072902.091907 · Cited by 1,093
DNMT1 and DNMT3b cooperate to silence genes in human cancer cells
Rhee, I., Bachman, K. E., Park, B. H., Jair, K.-W., Yen, R.-W. C., Schuebel, K. E., Cui, H., Feinberg, A. P., Lengauer, C., Kinzler, K. W., et al. (2002) · Nature · doi:10.1038/416552a · Cited by 1,039
Self-citationA silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin
Schotta, G., Lachner, M., Sarma, K., Ebert, A., Sengupta, R., Reuter, G., Reinberg, D., & Jenuwein, T. (2004) · Genes & Development · doi:10.1101/gad.300704 · Cited by 1,031
Self-citationStem Cells and Cancer: Two Faces of Eve
Clarke, M. F., & Fuller, M. T. (2006) · Cell · doi:10.1016/j.cell.2006.03.011 · Cited by 921
Cooperativity between DNA Methyltransferases in the Maintenance Methylation of Repetitive Elements
Liang, G., Chan, M. F., Tomigahara, Y., Tsai, Y., Gonzales, F. A., Li, E., Laird, P. W., & Jones, P. A. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.480-491.2002 · Cited by 570
Interplay between Two Epigenetic Marks
Johnson, L. M., Cao, X., & Jacobsen, S. E. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00976-4 · Cited by 479
Kuzmichev, A., Margueron, R., Vaquero, A., Preissner, T. S., Scher, M. B., Kirmizis, A., Ouyang, X., Brockdorff, N., Abate-Shen, C. T., Farnham, P., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409875102 · Cited by 418
Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa
Tamaru, H., Zhang, X., McMillen, D. A., Singh, P. B., Nakayama, J., Grewal, S. I. S., Allis, C. D., Cheng, X., & Selker, E. U. (2003) · Nature Genetics · doi:10.1038/ng1143 · Cited by 394
Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation
Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S.-H. L., Watkins, D. N., Herman, J. G., & Baylin, S. B. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020040 · Cited by 387
Self-citationNguyen, C. T., Weisenberger, D. J., Velicescu, M., Gonzales, F. A., Lin, J., Liang, G., & Jones, P. A. (2002) · PubMed · Cited by 383
Dependence of histone modifications and gene expression on DNA hypermethylation in cancer.
Fahrner, J. A., Eguchi, S., Herman, J. G., & Baylin, S. B. (2002) · PubMed · Cited by 353
Self-citationCritical Role of Histone Methylation in Tumor Suppressor Gene Silencing in Colorectal Cancer
Kondo, Y., Shen, L., & Issa, J. J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.206-215.2003 · Cited by 347
Jackson, J. P., Johnson, L. M., Jasencakova, Z., Zhang, X., Perez-Burgos, L., Singh, P. B., Cheng, X., Schubert, I. A., Jenuwein, T., & Jacobsen, S. E. (2004) · Chromosoma · doi:10.1007/s00412-004-0275-7 · Cited by 336
Self-citationMcGarvey, K. M., Fahrner, J. A., Greene, E., Martens, J. H. A., Jenuwein, T., & Baylin, S. B. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2481 · Cited by 285
Self-citationGarrison, F. H. (1926) · Europe PMC (PubMed Central) · Cited by 167
Effect of 5-Azacytidine on Gene Expression in Marrow Stromal Cells
Andrews, D. F., Nemunaitis, J. J., Tompkins, C., & Singer, J. W. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.6.2748-2751.1989 · Cited by 21
Effect of 5-azacytidine on gene expression in marrow stromal cells.
Andrews, D. F., Nemunaitis, J., Tompkins, C., & Singer, J. W. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.6.2748 · Cited by 13
Flagged first, then by citations
Cited by
Sorted by citations
Functions of DNA methylation: islands, start sites, gene bodies and beyond
Jones, P. A. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3230 · Cited by 6,061
Esteller, M. (2008) · New England Journal of Medicine · doi:10.1056/nejmra072067 · Cited by 3,767
Cancer epigenetics: from mechanism to therapy
Dawson, M. A., & Kouzarides, T. (2012) · Cell · doi:10.1016/j.cell.2012.06.013 · Cited by 3,203
CpG islands and the regulation of transcription
Deaton, A. M., & Bird, A. (2011) · Genes & Development · doi:10.1101/gad.2037511 · Cited by 3,187
A decade of exploring the cancer epigenome—biological and translational implications
Baylin, S. B., & Jones, P. A. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3130 · Cited by 2,871
Self-citation
Metadata
- Authors
- Ohm, J. E., McGarvey, K. M., Yu, X., Cheng, L., Schuebel, K. E., Cope, L., Mohammad, H. P., Chen, W., Daniel, V. C., Yu, W., Berman, D. M., Jenuwein, T., Pruitt, K., Sharkis, S. J., Watkins, D. N., Herman, J. G., & Baylin, S. B.
- Affiliations
- Johns Hopkins University (US)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Baylin, Stephen B
- ORCID
- Venue
- Nature Genetics
- Published
- 2007-01-09
- Volume
- 39
- Issue
- 2
- Pages
- 237-242
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2744394
- OpenAlex
- W2170210082
- Cited by
- 1,130
- References
- 30
- Citations by year
- 2026: 9 · 2025: 26 · 2024: 33 · 2023: 53 · 2022: 33 · 2021: 56 · 2020: 38 · 2019: 36 · 2018: 27 · 2017: 50 · 2016: 57 · 2015: 54 · 2014: 70 · 2013: 82 · 2012: 105
- FWCI
- 40.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl073781-10)
- Sidney Kimmel Comprehensive Cancer Center
- Sidney Kimmel Center for Prostate and Urologic Cancers
- National Heart, Lung, and Blood Institute (HL073781)
- National Cancer Institute (R01CA116160, CA116160, R01CA043318, CA 043318)
- 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 › Genetics › Genetic Syndromes and Imprinting
- Keywords
- tumor suppressor, DNA hypermethylation, chromatin, embryonic stem cells, embryonal carcinoma cells, H3K27 methylation, Polycomb group proteins, H3K4 methylation, H3K9 dimethylation, H3K9 trimethylation, CpG island hypermethylation, transcriptional silencing, stem cells, tumor initiation and progression
- MeSH terms
- Adult, Chromatin, Histones, Humans, Promoter Regions, Genetic, Repressor Proteins, Stem Cells, Tumor Cells, Cultured, Genes, Tumor Suppressor, DNA Methylation, Gene Silencing, Cell Proliferation, Embryonic Stem Cells, Polycomb-Group Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
