Environmentally Induced Epimutations, Their Persistence, and Potential Causality in the Development of Disease in the Offspring of Exposed Individuals

Abstract

In recent years, there has been increased interest into better understanding how environmental In recent years, there has been increased interest into better understanding how environmental exposures influence the long-term health of an organism. Chemical pollutants, dietary deficiencies, embryonic stress and multiple other external factors have all demonstrated long-lasting effects upon development, metabolism, and health even after transient exposures. The mechanisms by which these exposures can impact development far beyond the period of exposure remain largely unknown. To gain better insight into the developmental origins of both birth defects and disease, we must better understand how environmental exposures alter development.

In this work, we will examine the capacity of the environment to impact chromatin states, and then determine whether these changes are heritable; and are thus potentially causal in the development of disease. This is an important question due to the recent recognition that aberrant chromatin states can lead to pathological patterns of gene expression, a circumstance commonly referred to as “epimutations”. Dysregulation of gene expression patterns during development have been shown to cause a multitude of irregular phenotypes in offspring and lifelong disorders in mature organisms. This altered chromatin state, coined an epimutation by Dr. Emma Whitelaw, is important due to the mutation not being in the genetic code itself, but in the way DNA regulatory regions are packaged within the chromatin template, and thus accessed by the protein factors directing gene transcription. The body of work presented here will examine the ability of common environmental exposures to modulate chromatin structure. We will examine these changes over time in an effort to better understand the inheritance of epigenetic change. Secondly, we will measure whether environmentally induced alterations in chromatin structure within the germline persist, and are heritable. These questions are all relevant to better understanding the developmental origins of disease.