Chapter 062. Principles of Human Genetics (Part 6) The number of DNA sequences and transcription factors that regulate transcription is much greater than originally anticipated. Most genes contain at least 15–20 discrete regulatory elements within 300 bp of the transcription start site. This densely packed promoter region often contains binding sites for ubiquitous transcription factors such as CAAT box/enhancer binding protein (C/EBP), cyclic AMP response element–binding (CREB) protein, selective promoter factor 1 (Sp-1), or activator protein 1 (AP-1). However, factors involved in cell-specific expression may also bind to these sequences. For example, basic helix-loop-helix (bHLH) proteins bind to E-boxes in the promoters of myogenic genes, and steroidogenic factor 1 (SF-1) binds to a specific recognition site in the regulatory region of multiple steroidogenic enzyme genes. Key regulatory elements may also reside at a large distance from the proximal promoter. The globin and the immunoglobulin genes, for example, contain locus control regions that are several kilobases away from the structural sequences of the gene. Specific groups of transcription factors that bind to these promoter and enhancer sequences provide a combinatorial code for regulating transcription. In this manner, relatively ubiquitous factors interact with more restricted factors to allow each gene to be expressed and regulated in a unique manner that is dependent on developmental state, cell type, and numerous extracellular stimuli. As described below, the transcription factors that bind to DNA actually represent only the first level of regulatory control. Other proteins—coactivators and co-repressors— interact with the DNA-binding transcription factors to generate large regulatory complexes. These complexes are subject to control by numerous cell-signaling pathways, including phosphorylation, acetylation, sumoylation, and ubiquitinylation. Ultimately, the recruited transcription factors interact with, and stabilize, components of the basal transcription complex that assembles at the site of the TATA box and initiator region. This basal transcription factor complex consists of >30 different proteins. Gene transcription occurs when RNA polymerase begins to synthesize RNA from the DNA template. Mutations can occur in all domains of a gene (Fig. 62-4). A point mutation occurring within the coding region leads to an amino acid substitution if the codon is altered. Point mutations that introduce a premature stop codon result in a truncated protein. Large deletions may affect a portion of a gene or an entire gene, whereas small deletions and insertions alter the reading frame if they do not represent a multiple of three bases. These "frameshift" mutations lead to an entirely altered carboxy terminus. Mutations occurring in regulatory or intronic regions may result in altered expression or splicing of genes. Examples are shown in Fig. 62-5. Figure 62-4 Point mutations causing β-thalassemia as example of allelic heterogeneity. The β-globin gene is located in the globin gene cluster. Point mutations can be located in the promoter, the CAP site, the 5'-untranslated region, the initiation codon, each of the three exons, the introns, or the polyadenylation signal. Many mutations introduce missense or nonsense mutations, whereas others cause defective RNA splicing. Not shown here are deletion mutations of the β- globin gene or larger deletions of the globin locus that can also result in thalassemia., Promoter mutations; *, CAP site;, 5'UTR;1 , Initiation codon;, Defective RNA processing;, Missense and nonsense mutations;A, Poly A signal. Figure 62-5 A. Examples of mutations. The coding strand is shown with the encoded amino acid sequence. B. Chromatograms of sequence analyses after amplification of genomic DNA by polymerase chain reaction. . Chapter 062. Principles of Human Genetics (Part 6) The number of DNA sequences and transcription factors that regulate transcription. stabilize, components of the basal transcription complex that assembles at the site of the TATA box and initiator region. This basal transcription factor complex consists of >30 different. Figure 62-5 A. Examples of mutations. The coding strand is shown with the encoded amino acid sequence. B. Chromatograms of sequence analyses after amplification of genomic DNA by polymerase