The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
PcG Proteins, DNA Methylation, and Gene Repression by Chromatin Looping
Open accessAbstract
Many DNA hypermethylated and epigenetically silenced genes in adult cancers are Polycomb group (PcG) marked in embryonic stem (ES) cells. We show that a large region upstream ( approximately 30 kb) of and extending approximately 60 kb around one such gene, GATA-4, is organized-in Tera-2 undifferentiated embryonic carcinoma (EC) cells-in a topologically complex multi-loop conformation that is formed by multiple internal long-range contact regions near areas enriched for EZH2, other PcG proteins, and the signature PcG histone mark, H3K27me3. Small interfering RNA (siRNA)-mediated depletion of EZH2 in undifferentiated Tera-2 cells leads to a significant reduction in the frequency of long-range associations at the GATA-4 locus, seemingly dependent on affecting the H3K27me3 enrichments around those chromatin regions, accompanied by a modest increase in GATA-4 transcription. The chromatin loops completely dissolve, accompanied by loss of PcG proteins and H3K27me3 marks, when Tera-2 cells receive differentiation signals which induce a approximately 60-fold increase in GATA-4 expression. In colon cancer cells, however, the frequency of the long-range interactions are increased in a setting where GATA-4 has no basal transcription and the loops encompass multiple, abnormally DNA hypermethylated CpG islands, and the methyl-cytosine binding protein MBD2 is localized to these CpG islands, including ones near the gene promoter. Removing DNA methylation through genetic disruption of DNA methyltransferases (DKO cells) leads to loss of MBD2 occupancy and to a decrease in the frequency of long-range contacts, such that these now more resemble those in undifferentiated Tera-2 cells. Our findings reveal unexpected similarities in higher order chromatin conformation between stem/precursor cells and adult cancers. We also provide novel insight that PcG-occupied and H3K27me3-enriched regions can form chromatin loops and physically interact in cis around a single gene in mammalian cells. The loops associate with a poised, low transcription state in EC cells and, with the addition of DNA methylation, completely repressed transcription in adult cancer cells.
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Citations
Cites
High-Resolution Profiling of Histone Methylations in the Human Genome
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A bivalent chromatin structure marks key developmental genes in embryonic stem cells
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Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
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Self-citationBracken, A. P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Mönch, K., Minucci, S., Porse, B. T., Marine, J.-C., et al. (2007) · Genes & Development · doi:10.1101/gad.415507 · Cited by 850
Quantitative analysis of chromosome conformation capture assays (3C-qPCR)
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“PCR-based assay for analyzing restriction digestion efficiency as done previously by others [23,25,40,43,44] .”
MethodCTCF mediates long-range chromatin looping and local histone modification in the β-globin locus
Splinter, E., Heath, H., Kooren, J., Palstra, R.-J., Klous, P., Grosveld, F., Galjart, N., & de Laat, W. (2006) · Genes & Development · doi:10.1101/gad.399506 · Cited by 677
The β-globin nuclear compartment in development and erythroid differentiation
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Self-citationMethyl CpG-binding proteins and transcriptional repression
Wade, P. A. (2001) · BioEssays · doi:10.1002/bies.10008 · Cited by 351
Cited by
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-citationEDC-2: the endocrine society's second scientific statement on endocrine-disrupting chemicals
Gore, A. C., Chappell, V. A., Fenton, S. E., Flaws, J. A., Nadal, A., Prins, G. S., Toppari, J., & Zoeller, R. T. (2015) · Endocrine Reviews · doi:10.1210/er.2015-1010 · Cited by 2,407
Modification of Enhancer Chromatin: What, How, and Why?
Calo, E., & Wysocka, J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.038 · Cited by 1,457
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Ernst, T., Chase, A. J., Score, J., Hidalgo-Curtis, C. E., Bryant, C., Jones, A. V., Waghorn, K., Zoi, K., Ross, F. M., Reiter, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.621 · Cited by 1,139
Open chromatin in pluripotency and reprogramming
Gaspar-Maia, A., Alajem, A., Meshorer, E., & Ramalho-Santos, M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3036 · Cited by 573
Metadata
- Authors
- Tiwari, V. K., McGarvey, K. M., Licchesi, J. D. F., Ohm, J. E., Herman, J. G., Schübeler, D., & Baylin, S. B.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-12-02
- Volume
- 6
- Issue
- 12
- Pages
- e306
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- OpenAlex
- W2063682537
- Cited by
- 207
- References
- 14
- FWCI
- 10.05
- Type
- journal article
- Language
- en
- Open access
- gold
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