|Figure 1. Conrad H. Waddington 1905-1975|
... that epigenetic mechanisms were responsible for the developmental differentiation of cellular phenotypes?
The term epigenetics was first introduced by Conrad H. Waddington, an experimental embryologist, based on observations he made during the 1930's.
The Greek prefix epi- stands for above, and, literally translated, epigenetics means above genetics. Waddington described an intricate interplay between the cellular environment and genes having lasting effects on phenotype determination. Waddington was initially influenced by Spemann's experiments published in 1924 where he was able to induce the formation of a second head in amphibian embryos via allogenic injection of ooplasm from recently fertilized eggs. Waddington visited the Strangeways Laboratory to learn the watchglass technique of embryonic organ culture used by Fell and Robison . By extending this culture method to avian and mammalian embryos, Waddington was able to demonstrate the causal interplay between the embryonic layers during development .
Waddington's concepts of developmental mechanisms challenged the dogmas surrounding preformationism and Mendelian inheritance mechanisms that were popular at the time. Some believed the entire human being was preformed in the sperm and the female was merely a vessel for carriage and growth. Mendelian inheritance studies challenged this concept by examining traits and how they are inherited in offspring. Geneticists took these concepts further, proposing a gene centric view that persists as a central dogma of biological science whereby the genotype determines the phenotype. Waddington challenged this view with the advent of a new term he called epigenetics. The imprint of the cellular environment on the genome determines the phenotype. In fact, Waddington was correct; lasting genomic control determining phenotype is the mechanism by which a single cell having one genome becomes an entire multicellular organism . Moreover, this epigenetic imprint is maintained through cellular divisions. These concepts were remarkable considering that composition and structure of genes had yet to be discovered.
With the completion of the human genome project, modern epigeneticists have begun to elucidate the molecular mechanisms responsible for selectively expressing and silencing genes important for cellular phenotype specification (DNA methylation and histone posttranslational modifications). These efforts have led to a modern definition of epigenetics which describes reversible, heritable changes in gene function in the absence of changes in primary DNA sequence. In the lung, epigenetic targets have begun to show a promising avenue for treatment strategies in diseases such as cancer. Recent studies utilizing methylation specific PCR have been used to identify the methylation status of genes involved in lung cancer development . These studies show a direct correlation with promoter hypermethylation and silenced tumor suppessor genes, upstream transcription factors and DNA repair enzymes . Current cancer therapies are under development targeting DNA methylation and histone acetylation. Phase I/II studies using combination therapy of a histone deacetylase inhibitor and an inhibitor of DNA methylation in leukemia patients have revealed reactivation of p15, a tumor suppressor gene, in these patients . This results in varying degrees of remission and improved survival rates . A better appreciation of lung epigenotypes will enhance our understanding of lung development and repair as well as influence treatment strategies in epigenetic promoted lung disease.
This article written by Jennifer Clark, Oct. 2006.
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