CpG islands in their promoters appears to be especially important in progression to cancer (see methylation of DNA repair genes in cancer). Canonical sequences and wild-type The usage of the term canonical sequence to refer to a promoter is often problematic, and can lead to misunderstandings about promoter sequences. Canonical implies perfect, in some sense. In the case of a transcription factor binding site, there may be a single sequence that binds the protein most strongly under specified cellular conditions. This might be called canonical. However, natural selection may favor less energetic binding as a way of regulating transcriptional output. In this case, we may call the most common sequence in a population the wild-type sequence. It may not even be the most advantageous sequence to have under prevailing conditions. Recent evidence also indicates that several genes (including the proto-oncogene c-myc) have G-quadruplex motifs as potential regulatory signals. Synthetic promoter design and engineering Promoters are important gene regulatory elements used in tuning synthetically designed genetic circuits and metabolic networks. For example, to overexpress an important gene in a network, to yield higher production of target protein, synthetic biologists design promoters to upregulate its expression. Automated algorithms can be used to design neutral DNA or insulators that do not trigger gene expression of downstream sequences. Diseases that may be associated with variations Some cases of many genetic diseases are associated with variations in promoters or transcription factors. Examples include: Asthma Beta thalassemia Rubinstein-Taybi syndrome Constitutive vs regulated Some promoters are called constitutive as they are active in all circumstances in the cell, while others are regulated, becoming active in the cell only in response to specific stimuli. Use of the term When referring to a promoter some authors actually mean promoter + operator; i.e., the lac promoter is IPTG inducible, meaning that besides the lac promoter, the lac operon is also present. If the lac operator were not present the IPTG would not have an inducible effect. Another example is the Tac-Promoter system (Ptac). Notice how tac is written as a tac promoter, while in fact tac is actually both a promoter and an operator. See also Activator (genetics) Enhancer (genetics) Glossary of gene expression terms Operon Regulation of gene expression Repressor Transcription factor Promoter bashing References External links ORegAnno – Open Regulatory Annotation Database Identifying a Protein Binding Sites on DNA molecule YouTube tutorial video Pleiades Promoter Project – a