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Updated: May 3, 2026
Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
PRC2-independent chromatin compaction and transcriptional repression in cancer
C Vallot1, A Hérault1, S Boyle2
11] CNRS, UMR 144 - Cell Biology Department, Institut Curie, Paris, France [2] Institut Curie, Centre de Recherche, Paris, France.
Abstract:
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.
Insights
Epigenetic silencing in cancer involves chromatin compaction, not just H3K27 trimethylation. Targeting chromatin structure, rather than EZH2 alone, may be key for epigenetic cancer therapies.
Area of Science:
- Epigenetics
- Cancer Biology
- Chromatin Biology
Background:
- Epigenetic mechanisms frequently silence large chromosomal regions in cancer.
- Alterations in histone methylation and acetylation are observed at these loci.
- Mechanisms driving aberrant gene cluster formation remain poorly understood.
Purpose of the Study:
- To investigate the relationship between epigenetic silencing, chromatin structure, and gene expression in cancer.
- To determine the role of histone H3K27 trimethylation and chromatin compaction in cancer-associated gene silencing.
- To explore the therapeutic implications of these findings for epigenetic drug selection.
Main Methods:
- Fluorescence in situ hybridization (FISH) to analyze higher-order chromatin structures.
- Experimental manipulation of EZH2 levels (knockdown) to assess its impact on gene expression and chromatin compaction.
- Treatment with histone deacetylase (HDAC) inhibitors to evaluate effects on chromatin structure and gene repression.
Main Results:
- Epigenetic silencing of large chromosomal regions in cancer correlates with the formation of compact chromatin domains.
- Gene repression is tightly linked to chromatin compaction, independent of H3K27 trimethylation levels.
- Reducing H3K27 trimethylation (via EZH2 knockdown) did not restore gene expression or decompact chromatin.
- Transcription can persist even with high H3K27 trimethylation levels.
- Histone deacetylase inhibition relieved compaction and repression without altering H3K27 trimethylation.
Conclusions:
- Chromatin compaction, not solely PRC2 deregulation or H3K27me3 levels, drives the repression of large domains in cancer.
- EZH2's role in aberrant gene silencing in cancer may be less direct than previously thought.
- Therapeutic strategies targeting chromatin compaction could be beneficial for epigenetic alterations in cancer.
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