Epigenetic modifications as new targets for liver disease therapies

[摘要] An important discovery from the human genome mapping project was that it is comprised of a surprisingly low number of genes, with recent estimates suggesting they are as few as 25,000 [1]. This supported an alternative hypothesis that our complexity in comparison with lower order species is likely to be determined by regulatory mechanisms operating at levels above the fundamental DNA sequences of the genome [2]. One set of mechanisms that dictate tissue and cellular complexity can be described by the overarching term epigenetics''. In the 1940s, Conrad Waddington described epigenetics as the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being''. Today we understand epigenetics as a gene regulatory system comprised of 3 major mechanisms including DNA modifications (e.g., methylation), use of histone variants and post-translational modifications of the amino acid tails of histones and non-coding RNAs of which microRNAs are the best characterized [3,4]. Together, these mechanisms orchestrate numerous sets of chemical reactions that switch parts of the genome on and off at specific times and locations. Epigenetic marks, or the epigenome, exhibit a high degree of cellular-specificity and developmental or environmentally driven dynamic plasticity. Due to being at the interface between genome and the environment, the epigenome evolves at a very high rate compared to genetic mutations. Indeed, the differences in the epigenome account for most of the phenotypic uniqueness between closely related species, especially primates. More interestingly, the epigenetic changes, or epimutations, within an individual are not only maintained over cellular generations, but may also be transmitted between generations, such that adaptive epimutations generated in response to a particular environmental cue can influence phenotypes in our children and grandchildren [5].

[发布日期] 2013-12-01

[关键词] Epigenetic modifications;Liver disease;Chromatin;microRNA