Methylation‐mediated Transcriptional Silencing in Tumorigenesis

Abstract

Deoxyribonucleic acid (DNA) methylation of promoter CpG (cytosine/guanine) islands is a process that inhibits the expression of genes through mechanisms that interfere with transcriptional initiation. Transcriptional silencing occurs when the 5′ flanking DNA region becomes heavily methylated, either allowing transcriptional repressor proteins to directly bind to the methylated DNA region or causing a conformational change in the DNA sequence. Thus, the downstream consequence of DNA methylation is to interfere with the binding and activational activity of specific transcription factors required for gene expression. The effect of DNA hypermethylation is therefore to inhibit or reduce the expression potential of a target gene. The role of methylation in cancer has been determined by association studies where the promoter regions of tumour suppressor genes have been found to be highly methylated. This is followed by gene silencing and an increase in tumour growth. Clinical interest in the treatment of tumours has gained increased impetus because recent evidence on the use of novel therapeutic agents suggests that DNA promoter methylation is potentially reversible. This may thus allow for the development of future therapeutic intervention.

Key Concepts:

  • Epigenetic methylation is a key mechanism that can inhibit or reduce gene expression in the absence of DNA sequence variations.

  • Aberrant DNA methylation may downregulate a gene as effectively as a pathological mutation.

  • CpG island methylation of tumour suppressor gene promoter regions is a mechanism responsible for silencing gene expression leading to tumour development.

  • Methylation of CpG islands can occur in regions of DNA that reside at great distances from a target gene but still lead to a reduction in gene expression.

  • Aberrant methylation of tumour suppressor genes is potentially reversible in tumours allowing for therapeutic intervention.

Keywords: promoter; epigenetic; hypermethylation; tumour suppressor; carcinogenesis; CpG island

Figure 1.

(a) Representation of cytosine methylation and (b) methylation of the 5′‐cytosine phosphodiester bonded to guanine. m, methylation of the cytosine base.

Figure 2.

Mechanisms of methylation‐mediated repression: (a) no CpG methylation allows for transcription factor binding and expression of protein X; (b) hypermethylation of CpG dinucleotides directly prevents the access of transcription factors thereby inhibiting the expression of protein X and (c) another mechanism of hypermethylation‐mediated transcriptional repression is the recruitment of methylated CpG‐specific transcription factor‐blocking proteins. N, any base.

Figure 3.

Effects of methylation on chromatin conformation: (a) normal conformation; both the promoter and coding region are unmethylated, allowing normal expression; (b) hypermethylation of the coding region causes a structural change in chromatin conformation that spreads to the promoter, reducing transcription factor access, thereby blocking or reducing expression and (c) butyrate addition relaxes the hypermethylated DNA structure and allows the protein to be re‐expressed.

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Web Links

von Hippel‐Lindau syndrome (VHL); LocusID: 7428. LocusLink http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?1=7428

von Hippel‐Lindau syndrome (VHL); MIM number: 193300. OMIM http://www3.ncbi.nlm.nih.gov/Omim/193300

Retinoblastoma (including osteosarcoma) (RB1); LocusID: 5925. LocusLink http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?1=5925

Retinoblastoma (including osteosarcoma) (RB1); MIM number: 180200. OMIM http://www.ncbi.nlm.nih.gov/Omim/180200

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Horan, Martin P(Feb 2011) Methylation‐mediated Transcriptional Silencing in Tumorigenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005916.pub2]