Fine tuning gene expression: the epigenome

Abstract

An epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Epigenetic modifications such as DNA methylation, together with covalent modification of histones, are thought to alter chromatin density and accessibility of the DNA to cellular machinery, thereby modulating the transcriptional potential of the underlying DNA sequence. As environmental changes influence epigenetic marks, epigenetics provides an added layer of variation that might mediate the relationship between genotype and internal and external environmental factors. Integration of our knowledge in genetics, epigenomics, and genomics with the use of systems biology tools may present investigators with new, powerful tools to study many complex human diseases such as kidney disease.

Figure 1. The effect of different external signals depends on epigenetic modification in the target cells

The cellular response to external signals may reflect chromatin-based (epigenetic) differences superimposed on the static genetic code. In this example, the 5-regulatory region of a disease susceptibility gene is depicted in cells. While in some cells the promoter assumes an “open” chromatin architecture characterized by activating histone posttranslational marks, decreased nucleosome density, and the lack of DNA methylation. RNA polymerase II is recruited to the promoter, resulting in productive transcription. Alternatively, in other cells the genetically identical promoter assumes a “closed” chromatin configuration characterized by repressive posttranslational marks, increased nucleosome density, and prominent DNA methylation. RNA polymerase II is not recruited to the promoter, and no transcription occurs. Transcriptionally Competenent Euchromatin is usually associated with umethylated DNA, and trimethyl H3K9 and H3K23 marks. Transcriptionally Incompetent Heterochromatin is generally associated with methylated DNA and trimethyl H3K4 and H3K6 marks.

Figure 2. The complex Interaction between Genotype and Phenotype Development

During normal development somatic cells that descended from a single progenitor, and contain similar genotype, differentiate to acquire diverse biological function by expressing and repressing different set of genes via establishing new epigenetic marks. While the genotype of an individual does not change hyperglycemia, uremia, different dietary and environmental factors might change the epigenome of cells leading to differences in gene and protein expression. Differences in the epigenotype might be response for the different (including disease) phenotype development. While the genotype is stable there is a more dynamic link between environmental factors and phenotype development.