The proper regulation of gene expression is of fundamental importance in the maintenance of normal growth and development. Misregulation of genes can lead to such outcomes as cancer, diabetes and neurodegenerative disease. A key step in gene regulation occurs during the transcription of the chromosomal DNA into messenger RNA by the enzyme, RNA polymerase II.
Global mapping of the human epigenome has revealed that normal somatic cells exhibit their own unique DNA methylation patterns1. This tissue-specific methylome is established during development and faithfully maintained through subsequent cell divisions, in a process mediated by the enzymes DNMT1 and DNMT3A6. In recent years, there has been a growing interest in the influence of environmental factors in the establishment and maintenance of DNA methylation4. Many studies have implicated environmental exposure in promoting DNA methylation changes – thereby contributing to alterations in cellular phenotype and disease susceptibility2,8. The reliance of these studies on large epidemiological approaches and in vitro models, however, limits our ability to determine the direct causal relationship between the environment and the human epigenome.
In mammals, the Y chromosome is responsible for determining the male sex by initiating the development of male-specific gonad tissues. Hormones, produced and secreted by the sex organs, are vital for initiating and maintaining sexual dimorphisms. However, differences seen between the sexes are not solely derived from hormones. In fact, sexual differentiation begins in early embryonic development – before hormones have even begun to be produced. Some genes on both autosomal and sex chromosomes are differentially expressed between the sexes, prior to gonad differentiation.2,5 In embryonic stem cells, a XX sex compliment is associated with decreased global DNA methylation compared to XY and X0 cells.15 Sex compliments (XX vs XY) also influences the imprinting of autosomal alleles.6
Atherosclerosis is an inflammatory disease of the arterial walls, and is the major cause of heart attack and stroke. Atherosclerosis is localized to curves and branches in the vasculature where disturbed blood flow (d-flow) is able to alter gene expression and induce endothelial cell (EC) dysfunction. Our lab’s work focuses on the mechanism by which these gene expression changes occur. We utilize in vivo mouse models of d-flow-induced atherosclerosis that we have developed to determine how blood flow affects vascular biology and disease.2,3