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...
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Chapter 062. Principles of Human Genetics (Part 6) Chapter 062. Principles of Human Genetics (Part 6) The number of DNA sequences and transcription factors that regulatetranscription is much greater than originally anticipated. Most genes contain atleast 15–20 discrete regulatory elements within 300 bp of the transcription startsite. This densely packed promoter region often contains binding sites forubiquitous transcription factors such as CAAT box/enhancer binding protein(C/EBP), cyclic AMP response element–binding (CREB) protein, selectivepromoter factor 1 (Sp-1), or activator protein 1 (AP-1). However, factors involvedin cell-specific expression may also bind to these sequences. For example, basichelix-loop-helix (bHLH) proteins bind to E-boxes in the promoters of myogenicgenes, and steroidogenic factor 1 (SF-1) binds to a specific recognition site in theregulatory region of multiple steroidogenic enzyme genes. Key regulatoryelements may also reside at a large distance from the proximal promoter. Theglobin and the immunoglobulin genes, for example, contain locus control regionsthat are several kilobases away from the structural sequences of the gene. Specificgroups of transcription factors that bind to these promoter and enhancer sequencesprovide a combinatorial code for regulating transcription. In this manner,relatively ubiquitous factors interact with more restricted factors to allow eachgene to be expressed and regulated in a unique manner that is dependent ondevelopmental state, cell type, and numerous extracellular stimuli. As describedbelow, the transcription factors that bind to DNA actually represent only the firstlevel of regulatory control. Other proteins—coactivators and co-repressors—interact with the DNA-binding transcription factors to generate large regulatorycomplexes. These complexes are subject to control by numerous cell-signalingpathways, including phosphorylation, acetylation, sumoylation, andubiquitinylation. Ultimately, the recruited transcription factors interact with, andstabilize, components of the basal transcription complex that assembles at the siteof the TATA box and initiator region. This basal transcription factor complexconsists of >30 different proteins. Gene transcription occurs when RNApolymerase begins to synthesize RNA from the DNA template. Mutations can occur in all domains of a gene (Fig. 62-4). A point mutationoccurring within the coding region leads to an amino acid substitution if the codonis altered. Point mutations that introduce a premature stop codon result in atruncated 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 notrepresent a multiple of three bases. These frameshift mutations lead to anentirely altered carboxy terminus. Mutations occurring in regulatory or intronicregions may result in altered expression or splicing of genes. Examples are shownin Fig. 62-5. Figure 62-4 Point mutations causing β-thalassemia as example of allelicheterogeneity. The β-globin gene is located in the globin gene cluster. Pointmutations 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 polyadenylationsignal. Many mutations introduce missense or nonsense mutations, whereas otherscause 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 inthalassemia., Promoter mutations; *, CAP site;, 5UTR;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 encodedamino acid sequence. B. Chromatograms of sequence analyses after amplificationof genomic DNA by polymerase chain reaction.