The role of histone modifications in the reversal of abnormal gene silencing in cancer

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Johns Hopkins University
Two of the main mechanisms by which epigenetic changes can occur are DNA methylation and chromatin conformation changes. Aberrant hypermethylation of promoter CpG islands is associated with silencing of key genes in cancer. This silencing is thought to be mediated by chromatin remodeling complexes that are targeted to the hypermethylated DNA and alter the chromatin into a closed conformation. Repressive proteins in these complexes, such as histone deacetylases, are believed to further alter the chromatin by removing acetyl groups from histone tails. Thus histone tail modifications can help to change chromatin conformation. Another way in which chromatin can be altered is through replacement of core histones with variant histones, which can modify the functional properties of chromatin. We set out to define the relationship between aberrant DNA hypermethylation and chromatin conformation changes, specifically with respect to histone tail modifications and histone variants. We found that particular patterns of histone modifications are associated with a hypermethylated and an unmethylated promoter. Additionally, we studied the localization of an active transcription-associated histone variant and, preliminarily, found it enriched at the unmethylated, and not the hypermethylated, promoter The DNA demethylating agent 5-aza-2â -deoxycytidine (5-Aza-dC) can re-activate gene expression by reducing the extent of hypermethylation with each subsequent round of DNA replication. We wondered whether histone tail modification or histone replacement had a role in the 5-Aza-dC-induced re-expression of a tumor suppressor gene in cancer. Upon treatment with 5-Aza-dC, the pattern of histone modifications at the hypermethylated promoter were reversed to a pattern observed at the unmethylated promoter. Further examination led us to find that 5-Aza-dC demethylates the DNA, followed by gene re-expression, and thereafter by reversal of pattern of histone modifications. We determined that patterns of histone modifications and, possibly, enrichment of a histone variant can define an unmethylated, active gene or a hypermethylated, silenced gene. The pattern of histone modifications at the silenced gene is reversed when DNA demethylation is initiated, but only after DNA demethylation and gene re-expression occur first. Further study of histone replacement may reveal what role histone variants play in the re-activation of a gene silence with DNA hypermethylation.