Epigenetics in Cancer E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Life Science Research Fundamentals
• Sprache: Englisch

Seitenzahl: 321

Veröffentlichungsjahr: 2013

Beschreibung

Epigenetics is the study of heritable changes in gene expression or cellular phenotype, caused by mechanisms other than changes in the DNA sequence. Examples include DNA methylation and histone modification. These changes may remain through cell divisions and multiple generations. Epigenetic differences among individuals may account for some of the differences between monozygotic (identical) twins. Aberrant DNA methylation is also frequently associated with human aging and diseases, such as cancer. This collection of overviews and laboratory protocols provides crucial, distilled information about the roles of epigenetics in cancer development. The overviews are geared for research scientists who need to learn more about the current understanding of epigenetic variation in humans and how the processes of DNA methylation and histone modification are regulated. The protocols give step-by-step instructions on how to detect DNA methylation using various methods such as MAPit, CHARM (arrays) and methylation-specific PCR. This e-book -- a curated collection from eLS, WIREs, and Current Protocols -- offers a fantastic introduction to the fields of genetics, genomics, and oncogenesis for students or interdisciplinary collaborators.

Leseprobe

Epigenetics in Cancer

Introduction

Epigenetic Variation in Humans

Genetic and Epigenetic Heterogeneity in Cancer

Techniques and Applications

Mediators and dynamics of DNA methylation

DNA Methylation Alterations in Multiple Myeloma as a Model for Epigenetic Changes in Cancer

Ink4-Arf locus in cancer and aging

Protocols

Simultaneous Single-Molecule Mapping of Protein-DNA Interactions and DNA Methylation by MAPit

Comprehensive High-Throughput Arrays for Relative Methylation (CHARM)

Methylation-specific PCR

Further Reading

eLS

WIREs

Current Protocols

John Wiley & Sons, Ltd.

ELS subject area: Evolution and Diversity of Life

How to cite: Wilkins, Jon F (July 2008) Epigenetic Variation in Humans. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0020811

Advanced article

Epigenetic Variation in Humans

Jon F Wilkins, Santa Fe Institute, Santa Fe, New Mexico, USA

Epigenetic modifications alter the expression behaviour of genes without involving changes to the DNA (deoxyribonucleic acid) sequence itself. These modifications take a variety of forms, most notably DNA methylation and histone modification. Epigenetic differences allow alleles, cells or even individuals that are genetically identical to exhibit radically different phenotypes. Differentiation among cells underlies tissue differentiation and development. Differentiation between alleles within a cell is used to enhance clonal diversity, as in the immune system, and has been highjacked in the service of evolutionary genetic conflicts, as seen in the phenomenon of genomic imprinting. Epigenetic differences among individuals may account for some of the differences between monozygotic (identical) twins. Some recent studies have even suggested that these epigenetic mechanisms may allow organisms to adapt to environmental changes on very short timescales. Environmental adaptations could be epigenetically encoded and passed on to offspring, providing a potential mechanism for a neo-Lamarckian mode of evolution.

Introduction

Epigenetic mechanisms

There is more to a gene than its deoxyribonucleic acid (DNA) sequence. CH Waddington coined the term ‘epigenetic’ to describe biological differences among tissues resulting from the process of development (Waddington, 1939, 1942). Waddington needed a new term to describe this type of variation, which is not the product of genotypic differences among the cells. Neither are these tissue-level differences well described as phenotypic variation, since the variation occurs within an individual organism. We now understand that heritable modifications to the DNA (such as cytosine methylation) and aspects of chromatin structure (including histone modifications) are the mechanisms that underlie Waddington’s ‘epigenotype’. The DNA and its associated proteins are modified in particular cells during development, and those modifications are propagated across multiple cell divisions. Those modifications are responsible for the variation in patterns of gene expression across cell types. In contemporary usage, the term epigenetic refers to any heritable change in gene expression that is not coded in the DNA sequence itself (Egger et al., 2004).

In humans, there are two principal mechanisms of epigenetic modification. The first is cytosine methylation. This occurs overwhelmingly at CpG dinucleotides. These dinucleotides are found in clusters throughout the genome, known as CpG islands. The CpG dinucleotide is a simple example of a ‘pallindromic sequence’. That is, since C pairs with G, a CpG in one strand of the DNA is paired with another CpG in the complementary strand.

The propagation of methylation states across cell divisions depends on this pallindromic structure and the action of the protein Dnmt1, a maintenance methyltransferase, or hemimethylase. The fully methylated form has methyl groups attached to the cytosine on each strand. When the DNA is replicated, these two methylated strands are separated, and new (unmethylated) DNA is synthesized on each. The two daughter cells are then set to inherit hemimethylated DNA (DNA with methyl groups on one strand, but not the other). Dnmt1 specifically recognizes this hemimethylated DNA and attaches a methyl group to the newly synthesized strand. Thus, once the pattern of methylation is set in a particular cell, Dnmt1 acts to propagate this pattern to all of that cell’s descendants.