Organisms require an appropriate balance of stability and reversibility in gene expression programmes to maintain cell identity or to enable responses to stimuli; epigenetic regulation is integral to this dynamic control. Post-translational modification of histones by methylation is an important and widespread type of chromatin modification that is known to influence biological processes in the context of development and cellular responses. To evaluate how histone methylation contributes to stable or reversible control, we provide a broad overview of how histone methylation is regulated and leads to biological outcomes. The importance of appropriately maintaining or reprogramming histone methylation is illustrated by its links to disease and ageing and possibly to transmission of traits across generations.

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Histone methylation: a dynamic mark in health, disease and inheritance

This review describes new developments in the study of transgenerational epigenetic inheritance, a component of epigenetics. We start by examining the basic concepts of the field and the mechanisms that underlie epigenetic inheritance. We present a comprehensive review of transgenerational cellular epigenetic inheritance among different taxa in the form of a table, and discuss the data contained therein. The analysis of these data shows that epigenetic inheritance is ubiquitous and suggests lines of research that go beyond present approaches to the subject. We conclude by exploring some of the consequences of epigenetic inheritance for the study of evolution, while also pointing to the importance of recognizing and understanding epigenetic inheritance for practical and theoretical issues in biology.

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Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution

At present, transgenes in Caenorhabditis elegans are generated by injecting DNA into the germline. The DNA assembles into a semistable extrachromosomal array composed of many copies of injected DNA. These transgenes are typically overexpressed in somatic cells and silenced in the germline. We have developed a method that inserts a single copy of a transgene into a defined site. Mobilization of a Mos1 transposon generates a double-strand break in noncoding DNA. The break is repaired by copying DNA from an extrachromosomal template into the chromosomal site. Homozygous single-copy insertions can be obtained in less than 2 weeks by injecting approximately 20 worms. We have successfully inserted transgenes as long as 9 kb and verified that single copies are inserted at the targeted site. Single-copy transgenes are expressed at endogenous levels and can be expressed in the female and male germlines.

Single-copy insertion of transgenes in Caenorhabditis elegans.

Since the first description of RNA interference (RNAi) in animals less than a decade ago, there has been rapid progress towards its use as a therapeutic modality against human diseases. Advances in our understanding of the mechanisms of RNAi and studies of RNAi in vivo indicate that RNAi-based therapies might soon provide a powerful new arsenal against pathogens and diseases for which treatment options are currently limited. Recent findings have highlighted both promise and challenges in using RNAi for therapeutic applications. Design and delivery strategies for RNAi effector molecules must be carefully considered to address safety concerns and to ensure effective, successful treatment of human diseases.

Strategies for silencing human disease using RNA interference.

piRNAs Can Trigger a Multigenerational Epigenetic Memory in the Germline of C. elegans

Small RNA molecules participate in a variety of activities in the cell: in a process known as RNA interference (RNAi), double-stranded RNA triggers the degradation of messenger RNA that has a matching sequence; the small RNA intermediates of this process can also modify gene expression in the nucleus Here we show that a single episode of RNAi in the nematode Caenorhabditis elegans can induce transcriptional silencing effects that are inherited indefinitely in the absence of the original trigger Our findings may prove useful in the ongoing development of RNAi to treat disease

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Gene expression: long-term gene silencing by RNAi.

The DNA in a cell is prone to mutation. Since too many mutations are detrimental to the survival of a cell or an organism, special mechanism have developed to prevent and/or repair at least part of such mutations. Many of these mechanisms act before the mutation becomes fixed into the genome through replication of the DNA. Some of the genes involved in the prevention of mutations have been identified. However, prior to the invention there was no coherent and systematic way of doing so. The means and methods of the invention enable a person skilled in the art to determine whether a product of a gene is involved in the prevention of a mutation. Identified genes can be used to develop diagnostic tools or used as a target for drug development to manipulate cells on the basis of the presence or absence of function of this gene. Since DNA instability is one of the reasons for rapid tumor progression, it will be useful to provide cancer cells with additional product of such genes for instance through gene therapy.

Marcel Tijsterman

Papers

Gene expression: long-term gene silencing by RNAi.

Means and methods for identifying genes and proteins involved in the prevention and/or repair of a replication error