Editorial
 |
EPIGENETICS AND EPIGENOMES |
|---|
 TOP EPIGENETICS AND EPIGENOMES EPIGENETIC REGULATION OF GENE...EPIGENETIC RE-PROGRAMMING AND...EPIGENETICS AND CANCEREPIGENETIC MECHANISMSEPIGENETICS AND THE ENVIRONMENT |
|---|
Human Molecular Genetics is normally filled mostly with articles that relate changes in DNA sequence with disease pathologies. However, there has always been an appreciation in the journal that the regulation of gene expression and changes in chromatin structure also underpin normal human development and that perturbations of these can lead to disease.
The heritable changes in chromatin structure and gene expression that can be passed from one cell to its daughter cells fall under the umbrella term of ‘epigenetics’. Because DNA sequence alone does not describe our genetic information, a natural extension of the complete sequencing of the human genome is to ask whether we can also describe the ‘epigenome’, or more correctly the ‘epigenomes’, that even within one individual will vary between one somatic cell type and another and between normal and abnormal (e.g. cancer) cells. Therefore, it seems fitting that this special review issue on epigenetics should begin with a discussion of how the epigenome may be revealed and present an update on current progress.
Since the epigenome can vary between the genetically identical cells of one individual, it also may vary between two genetically identical, but separate, individuals (i.e. monozygotic twins). Arguing that the phenotypic differences between such twins might be attributable as much to epigenetic variation between them as to environmental influences, Wong et al. make us think about the contribution of epigenetics to etiologically complex, but common, diseases.
|
EPIGENETIC REGULATION OF GENE EXPRESSION IN NEURONS |
|---|
|
TOPEPIGENETICS AND EPIGENOMESEPIGENETIC REGULATION OF GENE...EPIGENETIC RE-PROGRAMMING AND...EPIGENETICS AND CANCEREPIGENETIC MECHANISMSEPIGENETICS AND THE ENVIRONMENT |
|---|
Contrasting with this broad-reaching question, Caballero and Hendrich focus on one disease, Rett Syndrome, where mutation of a single gene (MeCP2) is thought to disrupt the chromatin-based control of gene expression in the brain. Although there is extensive information on the molecular player involved, their review highlights how difficult it is to identify target genes that are subject to misregulation in the brain when MeCP2 is mutated, and how invaluable mouse models can be in reaching this goal.
Rett Syndrome is X-linked, and Skuse discusses the apparently disproportionate role of X-linked genes in mental functioning and how the expression of such genes may vary between males and females. Expression of only one allele of a gene is best exemplified by, but not limited to, X inactivation in females. Shykind describes a fascinating example of monoallelic expression of a family of autosomal genes—those that encode odorant receptors. Because activation of a single functional allele occurs in individual olfactory neurons, unravelling its mechanistic basis will be a major challenge, and will need to draw on more tractable systems.
|
EPIGENETIC RE-PROGRAMMING AND DEVELOPMENT |
|---|
|
TOPEPIGENETICS AND EPIGENOMESEPIGENETIC REGULATION OF GENE...EPIGENETIC RE-PROGRAMMING AND...EPIGENETICS AND CANCEREPIGENETIC MECHANISMSEPIGENETICS AND THE ENVIRONMENT |
|---|
Although all cells of the body essential contain the same DNA sequence, they express very different sets of genes. Epigenetics plays a central role in how these patterns of gene expression change during development. Perhaps because of the accessibility of the cells involved, the immune system has often lead the way in advancing our understanding of development and differentiation. Reiner illustrates this by describing how epigenetic effects can lead to a restriction in the gene expression programme, and its subsequent stabilization, in progeny cells, during the development of T helper cells.
Although epigenetics has an important role in altering patterns of gene expression during development, it is also important that these epigenetic modifications be reversible, especially when a change in the developmental potency of cells is needed. Morgan et al. describe the massive epigenetic re-programming that occurs naturally at the earliest stages of development, from zygote through to implantation of the blastocyst, and in the specification of the germline. They discuss not only possible mechanisms involved in reversing epigenetic marks, but also how re-programming may occur under artificial or experimental conditions (e.g. cloning). Similarly, Sado and Ferguson-Smith discuss how X chromosome inactivation is re-programmed in the first week of development in extra-embryonic versus embryonic tissues.
|
EPIGENETICS AND CANCER |
|---|
|
TOPEPIGENETICS AND EPIGENOMESEPIGENETIC REGULATION OF GENE...EPIGENETIC RE-PROGRAMMING AND...EPIGENETICS AND CANCEREPIGENETIC MECHANISMSEPIGENETICS AND THE ENVIRONMENT |
|---|
Just as epigenetic mechanisms are inherent to establishing and maintaining correct gene expression programmes during development, their inappropriate action also seems to be an important factor in cancer. Laird discusses how the study of cancer epigenetics can contribute not only to the understanding of cancer etiology, but also to its diagnosis and even therapy. Although correcting the genetic defects in cancer cells remains a difficult and distant goal of gene therapy, pharmacological intervention by inhibition of enzymes that modulate chromatin structure is a very real prospect and is the current focus of a number of clinical trials.
The role of misregulated chromatin structure in the etiology of cancer is perhaps most graphically illustrated by the number of chromatin-modifying proteins involved in leukaemia associated fusions, and is reviewed here by DiCroce. Many of these proteins are now known to enzymatically modify core histones. However, it is becoming clear that other enzymes, those that use the energy of ATP-hydrolysis to re-model nucleosomes, are also implicated in cancer and dysplastic syndromes (Gibbons). Other protein complexes, whose best-known roles are in the chromatin-mediated control of gene expression during development, also play a role in malignancies. Raaphorst discusses current insights into the role of polycomb proteins in the (mis)regulation of gene expression of important cell cycle regulators.
|
EPIGENETIC MECHANISMS |
|---|
|
TOPEPIGENETICS AND EPIGENOMESEPIGENETIC REGULATION OF GENE...EPIGENETIC RE-PROGRAMMING AND...EPIGENETICS AND CANCEREPIGENETIC MECHANISMSEPIGENETICS AND THE ENVIRONMENT |
|---|
Histone modification and nucleosome remodelling are well-established mechanisms in the chromatin-mediated control of gene expression. However, it is likely that higher order chromatin structure impacts gene expression. The intense scrutiny of genotype–phenotype correlations that occurs in the field of human molecular genetics has often been pivotal in exposing new mechanisms of gene regulation. A prime example of this was the part played by thalassaemia-associated deletions in pinpointing the ß-globin locus control region (LCR). The last few years have seen exciting new progress towards an understanding of how this, and other, long-range control elements regulate gene expression. In addition to clarifying some of the confusing terminology in the literature, West and Fraser introduce important new information in the mechanism of action of enhancers, LCRs, insulators and boundary elements.
Some of the most fascinating epigenetic phenomena in mammalian genetics (i.e. X inactivation and genomic imprinting) affect large clusters of genes. In both cases, non-coding RNAs, which are transcribed from a single allele, have been implicated in the mechanism of long-range gene silencing. O'Neill reviews the mechanism(s) by which this silencing occurs in these clusters and asks whether there are common mechanisms or themes. There is a revolution going on in our appreciation of the way that RNA can regulate gene expression, much of it driven by studies in simpler model organisms. Here, Mattick and Makunin review what is currently known about the role of small regulatory RNAs in mammals and how this rapidly advancing field is changing the way that we think about the non-genic parts of the human genome.
|
EPIGENETICS AND THE ENVIRONMENT |
|---|
|
TOPEPIGENETICS AND EPIGENOMESEPIGENETIC REGULATION OF GENE...EPIGENETIC RE-PROGRAMMING AND...EPIGENETICS AND CANCEREPIGENETIC MECHANISMSEPIGENETICS AND THE ENVIRONMENT |
|---|
In the context of cancer therapies, we have already discussed the possibility of intentionally inhibiting or subverting epigenetic mechanisms. However, there is also the possibility of unintentional perturbation of epigenetic pathways through medical practice, through what we eat or through environmental exposure. Maher highlights one recent area of concern: whether the practice of assisted reproduction, be it through effects on the egg, in vitro embryo culture or the consequence of infertility, increases the risk of imprinting defects in the resulting children.
We, and our epigenomes, are what we eat. As DNA (and histone) methylation depends on the co-factor SAM (or AdoMet), Ulrey et al. review the evidence that diet, and perturbation of one-carbon metabolism, can affect epigenetic marks both in the individual and also in the next generation. This issue ends with a hypothesis from Ruden et al. that other environmental chemicals might also impact on epigenetic states across generations, through as yet poorly understood mechanisms. Although impressive progress has already been made, it is clear that we have much to learn about how epigenetic mechanisms operate in mammalian development, how they are perturbed in disease and how we can manipulate them. Nevertheless, the tools are available, interest has been peaked and we eagerly anticipate future epigenetic breakthroughs.
|
ACKNOWLEDGEMENTS |
|---|
M.S.B is an investigator of the Howard Hughes Medical Institute and is supported by the National Institutes of Health. W.A.B is a centennial Fellow of the James S. McDonnell Foundation and is supported by the UK Medical Research Council and the European Union FP6 Epigenome Network of Excellence (LSHG-CT-2004–503433).
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Baba, M. Furihata, S.-B. Hong, L. Tessarollo, D. C. Haines, E. Southon, V. Patel, P. Igarashi, W. G. Alvord, R. Leighty, et al. Kidney-Targeted Birt-Hogg-Dube Gene Inactivation in a Mouse Model: Erk1/2 and Akt-mTOR Activation, Cell Hyperproliferation, and Polycystic Kidneys J Natl Cancer Inst, January 16, 2008; 100(2): 140 - 154. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||