Regulation of Gene Expression

  Genetics is a language that is subject to rules of composition, which confer particular traits on different tissues of the body. These rules are responsible for activating a specific subset of genes, which determines how each cell should divide, express its unique characteristics, or die. The molecular mechanisms responsible for activating a specific subset of genes, to determine how each cell should express its unique characteristics, are still only partially understood. The regulation of gene expression in various tissues is therefore a central focus of current research in molecular biology. The timing of gene expression is just as important as the proper selection of genes to be activated: a cell may miss a critical step in its development if the correct sequence of genes is not activated, and progression towards cancer is often marked by the inappropriate expression of a gene at the wrong time in the cell's cycle of division. During normal development, the absence of nkx2.5, a mammalian transcriptional regulatory factor expressed in the cardiac progenitors, results in a primitive heart tube that fails to loop correctly, suggesting that the genes controlled by nkx2.5 are crucial to the morphogenetic movements responsible for normal cardiac development.

  As we gain more understanding of gene regulation, we can devise clinically relevant experimental models. By introducing a mutated gene found in a particular human disease under the control of its normal regulatory DNA elements into the appropriate cell type, we can also study its altered function. For example, heart-targeted expression of a transgene encoding a mutant form of the cAMP response element binding protein (CREB), a nuclear protein that controls gene expression in cardiac myocytes, results in dramatic impairments of cardiac function in neonatal animals, again underscoring the importance of gene regulation in normal cardiac function (we will discuss both of these examples in detail in the cardiac congenital defects lecture). Understanding the rules of usage is a necessary prerequisite for fluency in any language, and genetics is no exception. We are just beginning to learn these rules, which are encoded in the same DNA language as the genes themselves.