Melanoma Molecular Maps Projects



Title: Epigenetics of melanoma: a systematic databank
Legend: Epigenetics is defined as heritable changes in gene expression that are not accompanied by changes in DNA sequence. Epigenetic modifications are believed to play a significant role in development and progression of cancer [1,2], including melanoma [3,4]. There are two main categories of epigenetic mechanisms that affect mammalian gene expression at the chromatin level and fulfill the criterion of heritability: DNA methylation and histone modification. DNA methylation in the mammalian genome arises due to covalent addition of a methyl group to the 5′ position of cytosine in the context of the palindromic dinucleotide, CpG. This modification (which is crucial for mammalian development) is established and maintained by a family of DNA methyltransferases (DNMTs), DNMT1, DNMT3a and DNMT3b. There are two patterns of CpG methylation in normal human somatic cells: a majority of the genome (98%) in which CpGs are relatively sparse (on average 1 per 100 base pairs (bp)) but highly methylated (approximately 80% of all CpG sites), and a minor fraction (2%) that comprises short stretches of DNA (1,000 bp) with high CpG density (1 per 10 bp) and largely methylation-free, known as CpG islands (CGIs). Unmethylated CpG islands often localize to the transcriptional start sites of genes, while gene promoter hypemethylation is generally associated with gene expression silencing. Approximately 60% of human genes are associated with CpG islands, most of which were once thought to be unmethylated in all tissue types except in certain circumstances (e.g. genomic imprinting and X chromosome inactivation). However, it is clear that there are normal tissue-specific patterns of CpG island methylation and some CpG island are prone to progressive methylation during aging and during the development of certain diseases such as cancer, including melanoma. Some genes do not display typical patterns of CpG methylation and gene expression. For example, hTERT encodes the catalytic subunit of telomerase, is expressed in most of telomerase positive tumors and its promoter CpG island is hypermethylated in many cancers and hypomethylated in telomerase negative normal tissues. Recently, investigators have concluded that hTERT expression is induced when the hTERT CpG island is sufficiently hypermethylated to avoid binding of the CTCF repressor yet hypomethylated at certain CpGs thereby enabling the transcription complex to be formed [7]. Although much of the focus of cancer epigenetics is on the inactivation of tumor suppressor genes by promoter methylation, the earliest observations of aberrant methylation in human cancer identified DNA hypomethylation: in particular, investigators found that the global methylated cytosine content is often reduced in cancer [8]. One consequence of genome wide hypomethylation may be genomic instability, a characteristic of most cancers. Gene specific hypomethylation may be responsible of gene overexpression in cancer. Histones are globular proteins with protruding N-terminal tails that are the main site of biochemical modifications including acetylation, methylation, phosphorylation, and ubiquitination. The specificity of certain histone modifications to influence transcription led to the "histone code hypothesis" which predicts that histone modifications act sequentially or in combination to alter chromatin structure and form a code that may be read by nuclear factors. Lysine acetylation neutralizes the charge between DNA and histone tails and correlates with chromatin accessibility and transcriptional activity. Lysine methylation can have different effects depending on which residue is modified. Hypermethylated CpG islands of silenced tumor-suppressor genes are known to display a particular histone code characterized by deacetylation of histones H3 and H4, methylation of H3 lysine 9 (H3K9), H3 lysine 27 (H3K27), and H4 lysine 20 (H4K20), and demethylation of H3 lysine 4. On the other hand, methylation of histone H3 lysine 4 (H3K4) and H3 lysine 36 is associated with transcribed chromatin. Histone modifications also function to recruit other effector proteins. Acetylated lysines are recognized by bromodomains within nucleosome remodeling complexes. An interaction between methylated H3K4 and the chromodomain of the helicase Chd1 recruits activating complexes to chromatin. In contrast, methylated H3K9 and H3K27 are bound by heterochromatin protein 1 (HP1) and Polycomb-group (PcG) proteins, respectively, which mediate chromatin compaction. A given lysine can have up to three methyl groups, and this ?methyl state? can influence chromodomain binding. PcG proteins preferentially interact with trimethylated H3K27, while HP1 shows preference for both di- and trimethylated H3K9. The ability of chromatin modifications to facilitate aberrant DNA methylation highlights uncertainty as to the primacy of DNA methylation or histone modifications as initiators of aberrant epigenetic gene silencing during cancer development. REFERENCES: [1] Esteller M, N Engl J Med 2008, 358:1148-59. [2] Gal-Yam EN, Annu Rev Med 2008, 59:267-80. [3] Richards HW, Pigment Cell Melanoma Res 2009, 22:14-29. [4] Lipkin G, J Invest Dermatol 2008, 128:2152-5. [5] Schwabe M, Curr Pharm Biotechnol 2007, 8:382-7. [6] Rothhammer T, Pigment Cell Res 2007, 20:92-111. [7] Renaud S, Nucleic Acids Res 2007, 35:1245-56. [8] Feinberg AP, Nature 1983, 301:89-92
Author: The MMMP Team (updated: January 2009)

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