Regulatory DNA Elements

  The development of the sophisticated cloning procedures to isolate DNA from cells we discussed above has resulted in an ever-expanding repertoire of DNA fragments, which carry not only genes, but presumably include signals, buried in the surrounding DNA sequences, to control the expression of these genes. The primary level of control is the regulation of gene transcription into mRNA. From comparative sequence analysis it is evident that many genes share common consensus sequences found upstream of the transcription start site. They include an A/T-rich element, known as the "TATA box", and other sequence motifs lying within about 100 nucleotide bases from the gene. These sequences, collectively called the "promoter" of a gene, form binding sites for RNA polymerase and its numerous cofactors, and their position relative to the start site is relatively inflexible.

  By contrast, other regulatory DNA elements are found in unpredictable locations, often at a considerable distance from the transcription start site of a gene. These elements are called enhancers, reflecting their ability to enhance transcription from the gene promoter. Enhancers are often several hundred bases long, and although they also form binding sites for regulatory proteins, they differ from promoters in several important ways. First, the position and orientation of an enhancer sequence relative to the gene is flexible: enhancers can dramatically increase gene transcription from positions on either side of the gene, even from thousands of bases away. Second, unlike promoter elements, enhancers do not share extensive sequences in common, and therefore cannot be easily identified on the basis of DNA sequence data alone.

  Both promoter and enhancer elements exhibit a wide variety of activities, based on the specific regulatory factors that bind to them. Enhancers are often responsible for the aberrant expression of genes after the breaking and rejoining of chromosomes (translocations) associated with specific forms of cancer: if a normally quiescent oncogene is reshuffled next to a strong enhancer on the other side of the breakpoint, it may be activated in an inappropriate way. Some promoters and enhancers drive expression of their associated genes in many cell types, whereas others are active only in a limited number of cells, to ensure that the genes they control are expressed in a particular pattern. For example, the regulatory elements associated with the muscle creatine kinase gene (MCK) drive expression in both cardiac and skeletal muscle, whereas the promoter associated with the gene encoding cardiac troponin C drives expression exclusively in cardiac muscle, and the promoter associated with the myosin light chain 2 gene restricts expression to the cardiac ventricle.