Evidence from many sources shows that the control of gene expression in higher organisms is related to the methylation of cytosine in DNA, and that the pattern of methylation is inherited. Loss of methylation, which can result from DNA damage, will lead to heritable abnormalities in gene expression, and these may be important in oncogenesis and aging. Transformed permanent lines often lose gene activity through de novo methylation. It is proposed that epigenetic defects in germline cells due to loss of methylation can be repaired by recombination at meiosis but that some are transmitted to offspring.

https://science.sciencemag.org/content/sci/238/4824/163.full.pdf

The inheritance of epigenetic defects.

The essentials of DNA methylation.

High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines.

There is tremendous ferment in the field of epigenetics as the relationships between chromatin structure and DNA methylation patterns become clearer. Central to this activity is the realization that the 'histone code', which involves the post-translational modification of histones and which has important ramifications for chromatin structure, may be linked to the DNA cytosine methylation pattern. New discoveries have suggested that histone lysine 9 methylation is implicated in the spread of heterochromatin in Drosophila and other organisms. Very recently it has been found that histone lysine 9 methylation is also necessary for some DNA methylation in Neurospora and plants. There is therefore the possibility that these two processes are closely linked, suggesting ways in which DNA methylation patterns may be established during normal development. Understanding these processes is fundamental to understanding what goes awry during the process of aging and carcinogenesis where DNA methylation patterns become substantially altered and contribute to the malignant phenotype.

/pdf/dna-methylation-and-cancer-2oyizqlm12.pdf

DNA methylation and cancer.

A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). With the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. Despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. Yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. The phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. Moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. The significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. Epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. In addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. Here, we review the evidence available for the role epigenetics on host–pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host–pathogen studies. We conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.

/pdf/epigenetics-of-host-pathogen-interactions-the-road-ahead-and-3m5i3edyu0.pdf

Epigenetics of host-pathogen interactions: the road ahead and the road behind.

We report the isolation and characterization of a mammalian strain (tsm) that has a temperature-sensitive mutation in DNA methylation. The isolation procedure was based on the observation that treatment of a CHO TK- MT- cell line with demethylating agents introduces up to 46% demethylation, resulting in phenotypic reversion and transcriptional activation of the thymidine kinase (TK) and metallothionein (MT) genes at frequencies ranging from 1% to 59%. Seven thousand individual colonies from an EMS-mutagenized CHO TK- MT- population were screened for spontaneous reversion to TK+ phenotype after treatment at 39 degrees C. Successful isolates were subsequently examined for MT+ reversion. A single clone (tsm) was obtained that showed temperature-dependent reactivation of both TK and MT genes at frequencies of 7.2 X 10(-4) and 6 X 10(-4), respectively. The tsm cells were viable at 39 degrees C and showed no increased mutation frequency. Reactivation correlated with transcriptional activation of the respective genes, whereas backreversion to the TK- phenotype was associated with transcriptional inactivation. TK- backrevertants were reactivable again with demethylating agents. Although demethylation in tsm cells was not detectable by HPLC, Southern blot analysis revealed that reactivants, irrespective of their mode of generation, showed specific demethylation of both TK and MT genes. Also, after about 150 cell generations after treatment, reactivants from both temperature-induced tsm and cells exposed to demethylating agents gained 60% and 23%, respectively, in 5-methylcytosine (5mC). It is proposed that the phenotype of tsm cells is due to a mutation involved in the regulation of DNA methylation. The further characterization of this and other mammalian mutants should help to clarify the physiological role of DNA methylation, as well as its regulation.

/pdf/gene-reactivation-a-tool-for-the-isolation-of-mammalian-dna-3rdtif2abx.pdf

P A Jeggo

Papers

Gene reactivation: a tool for the isolation of mammalian DNA methylation mutants.