This article reviews the mechanisms of gene silencing in cancer and clinical applications of this phenomenon. The silencing of genes, especially tumor-suppressor genes, is a key event in the development of cancer. The silencing can be effected by a disabling mutation or by a shutting down of the promoter region, the site at which transcription of the gene begins.

Gene Silencing in Cancer in Association with Promoter Hypermethylation

Cytosine methylation is required for mammalian development and is often perturbed in human cancer. To determine how this epigenetic modification is distributed in the genomes of primary and transformed cells, we used an immunocapturing approach followed by DNA microarray analysis to generate methylation profiles of all human chromosomes at 80-kb resolution and for a large set of CpG islands. In primary cells we identified broad genomic regions of differential methylation with higher levels in gene-rich neighborhoods. Female and male cells had indistinguishable profiles for autosomes but differences on the X chromosome. The inactive X chromosome (Xi) was hypermethylated at only a subset of gene-rich regions and, unexpectedly, overall hypomethylated relative to its active counterpart. The chromosomal methylation profile of transformed cells was similar to that of primary cells. Nevertheless, we detected large genomic segments with hypomethylation in the transformed cell residing in gene-poor areas. Furthermore, analysis of 6,000 CpG islands showed that only a small set of promoters was methylated differentially, suggesting that aberrant methylation of CpG island promoters in malignancy might be less frequent than previously hypothesized.

Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells.

Epigenetic changes such as DNA methylation act to regulate gene expression in normal mammalian development. However, promoter hypermethylation also plays a major role in cancer through transcriptional silencing of critical growth regulators such as tumor suppressor genes. Other chromatin modifications, such as histone deacetylation and chromatin-binding proteins, affect local chromatin structure and, in concert with DNA methylation, regulate gene transcription. The DNA methylation inhibitors azacitidine and decitabine can induce functional re-expression of aberrantly silenced genes in cancer, causing growth arrest and apoptosis in tumor cells. These agents, along with inhibitors of histone deacetylation, have shown clinical activity in the treatment of certain hematologic malignancies where gene hypermethylation occurs. This review examines alteration in DNA methylation in cancer, effects on gene expression, and implications for the use of hypomethylating agents in the treatment of cancer.

DNA methylation and gene silencing in cancer

Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying this “developmental origins hypothesis” are poorly understood. This review focuses on the likely involvement of epigenetic mechanisms in the developmental origins of health and disease (DOHaD). We describe permanent effects of transient environmental influences on the developmental establishment of epigenetic gene regulation and evidence linking epigenetic dysregulation with human disease. We propose a definition of “epigenetic epidemiology” and delineate how this emerging field provides a basis from which to explore the role of epigenetic mechanisms in DOHaD. We suggest strategies for future human epidemiologic studies to identify causal associations between early ex...

Epigenetic epidemiology of the developmental origins hypothesis.

长期以来,对于肿瘤的发病机制,就存在两种意见,一种意见认为,肿瘤的发生是由于基因突变导致的遗传特性改变引起的,另一种意见认为,肿瘤的发生是由于基因表达的失调,即通过表遗传学机制引起的.只是近几十年来,由于癌基因与抑癌基因的发现及对之研究的巨大进步,使得肿瘤表遗传学的研究一直处于遗传学研究的阴影之下而已[1]。

Cancer epigenetics

Fruit weight and size are agriculturally important traits, but little is known of their genetic and molecular bases. Many genetic studies on these traits have been done in the tomato, owing to the disparity in size between the fruits of wild and domesticated tomatoes (see picture). Quantitative trait loci (QTL) mapping studies in this plant have identified nearly 30 tomato QTL that affect fruit weight and size. One such QTL is fw2.2, which accounts for ~30% of the difference in fruit weight between wild and domesticated tomatoes. Earlier studies have strongly indicated that altered gene regulation underlies the effects of the largeand small-fruit alleles of fw2.2 on fruit weight. It has long been believed that such mutations, especially when they affect the timing of development (‘heterochronic’ mutations), might be a natural force of evolutionary change in plants. In a detailed study of fw2.2, Steven Tanksley’s group now provide the first experimental evidence to support this theory. Because previous studies in plants and Drosophila have shown that both cell division and expansion are essential factors that determine organ and fruit size, Cong et al. analysed cell size and mitotic index (MI) in two nearly isogenic tomato lines in which either a largeor small-fruit fw2.2 allele was present. Differences in MI were found between the fruits of these two lines, but not in cell size. In the small-fruit fw2.2 line (TA1144), a rapid but brief rise in MI occurs immediately after fertilization. By contrast, a more gradual and sustained rise in MI occurs in the large-fruit allele line (TA1143), indicating that an extended period of cell division might underlie larger fruit size in this line. Next, the authors found that the fw2.2 alleles differ in the timing of their peak expression by around one week. This difference in expression timing inversely correlated with changes in mitotic activity during early fruit development, indicating that fw2.2 might negatively regulate cell division. Moreover, by ~12 days post-fertilization, fw2.2 levels in TA1144 were more than double those in TA1143. However, only subtle differences in expression patterns were evident between the two lines.

/pdf/behavioural-genetics-worms-gang-up-on-bacteria-3erlb53pvv.pdf

Behavioural genetics: Worms gang up on bacteria

Childhood trauma can predispose people with certain genotypes to disorders such as post-traumatic stress disorder in adulthood. Now, Klengel et al. show that a particular polymorphism in a gene involved in glucocorticoid regulation can interact with childhood trauma, leading to lasting epigenetic changes in the stress response system.

/pdf/neurogenetics-trauma-and-stress-from-child-to-adult-1cnuqv8fs1.pdf

Rachel Jones

Papers

Behavioural genetics: Worms gang up on bacteria

Neurogenetics: Trauma and stress, from child to adult.

Neurogenetics: Trauma and stress, from child to adult