PRC2-independent chromatin compaction and transcriptional repression in cancer.
The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high-H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations.
1] CNRS, UMR 144 - Cell Biology Department, Institut Curie, Paris, France [2] Institut Curie, Centre de Recherche, Paris, France.
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Vallot
1] CNRS, UMR 144 - Cell Biology Department, Institut Curie, Paris, France [2] Institut Curie, Centre de Recherche, Paris, France.
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Hérault
Chromosome and Gene Expression Section, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Scotland, UK.
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Boyle
1] Chromosome and Gene Expression Section, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Scotland, UK [2] Breakthrough Breast Cancer Research Unit, University of Edinburgh, Scotland, UK.
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Bickmore
1] CNRS, UMR 144 - Cell Biology Department, Institut Curie, Paris, France [2] Institut Curie, Centre de Recherche, Paris, France.
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Radvanyi
D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
D002843:Chromatin; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2