Epigenetic memory in development and disease: Unraveling the mechanism

Epigenetic memory is an essential process of life that governs the inheritance of predestined functional characteristics of normal cells and the newly acquired properties of cells affected by cancer and other diseases from parental to progeny cells. Unraveling the molecular basis of epigenetic memory dictated by protein and RNA factors in conjunction with epigenetic marks that are erased and re-established during embryogenesis/development during the formation of somatic, stem and disease cells will have far reaching implications to our understanding of embryogenesis/development and various diseases including cancer. While there has been enormous progress made, there are still gaps in knowledge which includes, the identity of unique epigenetic memory factors (EMFs) and epigenome coding enzymes/co-factors/scaffolding proteins involved in the assembly of defined “epigenetic memorysomes” and the epigenome marks that constitute collections of gene specific epigenetic memories corresponding to specific cell types and physiological conditions. A better understanding of the molecular basis for epigenetic memory will play a central role in improving diagnostics and prognostics of disease states and aid the development of targeted therapeutics of complex diseases.     

Epigenomics of cancer – emerging new concepts

The complexity of the mammalian genome is regulated by heritable epigenetic mechanisms, which provide the basis for differentiation, development and cellular homeostasis. These mechanisms act on the level of chromatin, by modifying DNA, histone proteins and nucleosome density/composition. During the last decade it became clear that cancer is defined by a variety of epigenetic changes, which occur in early stages of disease and parallel genetic mutations. With the advent of new technologies we are just starting to unravel the cancer epigenome and latest mechanistic findings provide the first clue as to how altered epigenetic patterns might occur in different cancers. Here we review latest findings on chromatin related mechanisms and hypothesize how their impairment might contribute to the altered epigenome of cancer cells.     

Aberrant epigenetic landscape in cancer: how cellular identity goes awry

Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of "resetting" the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed.     

A glimpse into the epigenetic landscape of gene regulation

Post-translational modifications to histone proteins and methylation of DNA comprise the epigenome of a cell. The epigenome, which changes through development, controls access to our genes. Recent advances in DNA sequencing technology has led to genome-wide distribution data for a limited number of histone modifications in mammalian stem cells and some differentiated lineages. These studies reveal predictive correlations between histone modifications, different classes of gene and chromosomal features. Moreover, this glimpse into our epigenome challenges current ideas about regulation of gene expression. Many genes in stem cells are poised for expression with initiated RNA polymerase II at the promoter. This state is maintained by an epigenetic mark through multiple lineages until the gene is expressed.     

Articles selected by Faculty of 1000: phage receptor-binding proteins; genetic diversity in Toxoplasma; ribosome biogenesis and cell size; gene regulation by retrotransposons; manipulation of the cancer epigenome

A selection of evaluations from Faculty of 1000 covering phage receptor-binding proteins; genetic diversity in Toxoplasma; ribosome biogenesis and cell size; gene regulation by retrotransposons; manipulation of the cancer epigenome.     

Expression of Polycomb Targets Predicts Breast Cancer Prognosis

Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding, breast cancer patients can be stratified into good and poor prognostic groups independent of known cancer gene signatures. The EZH2-bound regions were downregulated in tumors characterized by aggressive behavior, high expression of cell cycle genes, and low expression of developmental and cell adhesion genes. Depletion of EZH2 in breast cancer cells significantly increased expression of the top altered genes, decreased proliferation, and improved cell adhesion, indicating a critical role played by EZH2 in determining the cancer phenotype.     

Malaria: Could its unusual epigenome be the weak spot?

The epigenetic contribution to the regulation and maintenance of gene expression patterns by histone modifications is well established in eukaryotes. In Plasmodium falciparum, the mechanisms and factors regulating gene expression during progression through its infected red blood cell cycle (iRBC) and underlying mutually exclusive expression of antigenic variation genes involved in immune evasion are far from understood. Recently, the first comprehensive analyses of the P. falciparum chromatin landscape at different iRBC stages have been performed. These studies uncovered the existence of well-defined heterochromatic regions within a generally euchromatic epigenome. Notably, silencing of genes encoding for virulence determinants such as var genes, appears to be orchestrated by the concerted action of the Sir2 and HP1 orthologs and the presence of the histone mark, H3K9me3. Epigenetic speciation could make the parasite exquisitely vulnerable to epigenetic drug treatment, unless this deadly parasite still has a number of tricks up his sleeves.     

Chromatin plasticity in response to DNA damage: The shape of things to come

DNA damage poses a major threat to cell function and viability by compromising both genome and epigenome integrity. The DNA damage response indeed operates in the context of chromatin and relies on dynamic changes in chromatin organization. Here, we review the molecular bases of chromatin alterations in response to DNA damage, focusing on core histone mobilization in mammalian cells. Building on our current view of nucleosome dynamics in response to DNA damage, we highlight open challenges and avenues for future development. In particular, we discuss the different levels of regulation of chromatin plasticity during the DNA damage response and their potential impact on cell function and epigenome maintenance.     

EpiExplorer: live exploration and global analysis of large epigenomic datasets

Epigenome mapping consortia are generating resources of tremendous value for studying epigenetic regulation. To maximize their utility and impact, new tools are needed that facilitate interactive analysis of epigenome datasets. Here we describe EpiExplorer, a web tool for exploring genome and epigenome data on a genomic scale. We demonstrate EpiExplorer's utility by describing a hypothesis-generating analysis of DNA hydroxymethylation in relation to public reference maps of the human epigenome. All EpiExplorer analyses are performed dynamically within seconds, using an efficient and versatile text indexing scheme that we introduce to bioinformatics. EpiExplorer is available at http://epiexplorer.mpi-inf.mpg.de.     

Emerging patterns of epigenomic variation

Fuelled by new sequencing technologies, epigenome mapping projects are revealing epigenomic variation at all levels of biological complexity, from species to cells. Comparisons of methylation profiles among species reveal evolutionary conservation of gene body methylation patterns, pointing to the fundamental role of epigenomes in gene regulation. At the human population level, epigenomic changes provide footprints of the effects of genomic variants within the vast nonprotein-coding fraction of the genome, and comparisons of the epigenomes of parents and their offspring point to quantitative epigenomic parent-of-origin effects confounding classical Mendelian genetics. At the organismal level, comparisons of epigenomes from diverse cell types provide insights into cellular differentiation. Finally, comparisons of epigenomes from monozygotic twins help dissect genetic and environmental influences on human phenotypes and longitudinal comparisons reveal aging-associated epigenomic drift. The development of new bioinformatic frameworks for comparative epigenome analysis is putting epigenome maps within the reach of researchers across a wide spectrum of biological disciplines.     

DNA methylation aberrancies as a guide for surveillance and treatment of human cancers

DNA methylation aberrancies are hallmarks of human cancers and are characterized by global DNA hypomethylation of repetitive elements and non-CpG rich regions concomitant with locus-specific DNA hypermethylation. DNA methylation changes may result in altered gene expression profiles, most notably the silencing of tumor suppressors, microRNAs, endogenous retorviruses and tumor antigens due to promoter DNA hypermethylation, as well as oncogene upregulation due to gene-body DNA hypermethylation. Here, we review DNA methylation aberrancies in human cancers, their use in cancer surveillance and the interplay between DNA methylation and histone modifications in gene regulation. We also summarize DNA methylation inhibitors and their therapeutic effects in cancer treatment. In this context, we describe the integration of DNA methylation inhibitors with conventional chemotherapies, DNA repair inhibitors and immune-based therapies, to bring the epigenome closer to its normal state and increase sensitivity to other therapeutic agents to improve patient outcome and survival.     

Regulated noise in the epigenetic landscape of development and disease

In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After grounding our argument in a discussion of stochastic noise and nongenetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, thus contributing to tumor cell heterogeneity.