Cancer: the chromatin connection

The American Association for Cancer Research's 93rd Annual Meeting was held in San Francisco, California, USA, from 6 to 10 April 2002.     

Cancer genomics identifies disrupted epigenetic genes

Latest advances in genome technologies have greatly advanced the discovery of epigenetic genes altered in cancer. The initial single candidate gene approaches have been coupled with newly developed epigenomic platforms to hasten the convergence of scientific discoveries and translational applications. Here, we present an overview of the evolution of cancer epigenomics and an updated catalog of disruptions in epigenetic pathways, whose misregulation can culminate in cancer. The creation of these basic mutational catalogs in cell lines and primary tumors will provide us with enough knowledge to move diagnostics and therapy from the laboratory bench to the bedside.     

New and Xisting regulatory mechanisms of X chromosome inactivation

Equalization of X linked gene expression is necessary in mammalian cells due to the presence of two X chromosomes in females and one in males. To achieve this, all female cells inactivate one of the two X chromosomes during development. This process, termed X chromosome inactivation (XCI), is a quintessential epigenetic phenomenon and involves a complex interplay between noncoding RNAs and protein factors. Progress in this area of study has consequently resulted in new approaches to study epigenetics and regulatory RNA function. Here we will discuss recent developments in the field that have advanced our understanding of XCI and its regulatory mechanisms.     

Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype

Background

Tumor heterogeneity is a major obstacle for finding effective treatment of Glioblastoma (GBM). Based on global expression analysis, GBM can be classified into distinct subtypes: Proneural, Neural, Classical and Mesenchymal. The signatures of these different tumor subtypes may reflect the phenotypes of cells giving rise to them. However, the experimental evidence connecting any specific subtype of GBM to particular cells of origin is lacking. In addition, it is unclear how different genetic alterations interact with cells of origin in determining tumor heterogeneity. This issue cannot be addressed by studying end-stage human tumors.

Methodology/Principal Findings

To address this issue, we used retroviruses to deliver transforming genetic lesions to glial progenitors in adult mouse brain. We compared the resulting tumors to human GBM. We found that different initiating genetic lesions gave rise to tumors with different growth rates. However all mouse tumors closely resembled the human Proneural GBM. Comparative analysis of these mouse tumors allowed us to identify a set of genes whose expression in humans with Proneural GBM correlates with survival.

Conclusions/Significance

This study offers insights into the relationship between adult glial progenitors and Proneural GBM, and allows us to identify molecular alterations that lead to more aggressive tumor growth. In addition, we present a new preclinical model that can be used to test treatments directed at a specific type of GBM in future studies.     

SymRK and the nodule vascular system: An underground connection

Symbiotic legume-rhizobia relationship leads to the formation of nitrogen-fixing nodules. Successful nodulation depends on the expression and cross-talk of a batttery of genes, among them SymRK (symbiosis receptor-like kinase), a leucine-rich repeat receptor-like kinase. SymRK is required for the rhizobia invasion of root hairs, as well as for the infection thread and symbiosome formation. Using immunolocalization and downregulation strategies we have recently provided evidence of a new function of PvSymRK in nodulation. We have found that a tight regulation of PvSymRK expression is required for the accurate development of the vascular bundle system in Phaseolus vulgaris nodules.     

An epigenetic Tet a Tet with pluripotency

DNA and chromatin-modifying enzymes establish an ESC/iPSC-specific epigenomic landscape that is linked to a network of pluripotency genes and influences differentiation potential. In this issue of Cell Stem Cell, Koh?et?al. (2011) highlight Tet1 and Tet2 as key players in this network of coordinated genetic and epigenetic control.     

Protein kinase C-beta: An emerging connection between nutrient excess and obesity

There is currently a global epidemic of obesity as a result of recent changes in lifestyle. Excess body fat deposition is caused by an imbalance between energy intake and energy expenditure due to interactions between genetic and environmental factors. The signals and biological mechanisms that trigger fat accumulation by disrupting energy homeostasis are not well understood. There is considerable evidence now supporting a possible role of protein kinase C beta (PKCβ) in energy homeostasis. This review highlights recent findings on the role of PKCβ activation in the genesis and progression of obesity, and of PKCβ repression in mediating the beneficial effects of physical exercise. Available data support a model in which adipose PKCβ activation is among the initiating events that disrupt mitochondrial function through interaction with p66^shc and amplify fat accumulation and adipose dysfunction, with systemic consequences. Manipulation of PKCβ levels, activity, or signaling could provide a therapeutic approach to combat obesity and associated metabolic disorders.     

An epigenetic signature for monoallelic olfactory receptor expression

Constitutive heterochromatin is traditionally viewed as the static form of heterochromatin that silences pericentromeric and telomeric repeats in a cell cycle- and differentiation-independent manner. Here, we show that, in the mouse olfactory epithelium, olfactory receptor (OR) genes are marked in a highly dynamic fashion with the molecular hallmarks of constitutive heterochromatin, H3K9me3 and H4K20me3. The cell type and developmentally dependent deposition of these marks along the OR clusters are, most likely, reversed during the process of OR choice to allow for monogenic and monoallelic OR expression. In contrast to the current view of OR choice, our data suggest that OR silencing takes place before OR expression, indicating that it is not the product of an OR-elicited feedback signal. Our findings suggest that chromatin-mediated silencing lays a molecular foundation upon which singular and stochastic selection for gene expression can be applied.     

An epigenetic role for noncoding RNAs and intragenic DNA methylation

A report on the Keystone Symposium 'Epigenetics: Regulation of Chromatin Structure in Development and Disease', Breckenridge, USA, 11-16 April 2007.