Transcription promoters, enhancers

Structural studies of the chromatin organization of integrated HlV-1 have identified two DNase 1-Hypersensitive Sites (HS4 and HS7) outside of the promoter/enhancer region in U3, that were likely to play a role in controlling viral transcription by virtue of their accessibility in chromatin (Fig. la and lb) (Verdin, 1991). 

In the nucleus, the hormone-receptor complex binds to nucleotide sequences known as hormone response elements (HREs). These are short palindromic DNA segments that usually promote transcription as enhancer elements (see p. 244). The illustration shows the HRE for glucocorticoids (GRE ... 

Once integrated into the host chromosome, the assembly of new viral particles necessitates the prodnction of viral RNA transcripts and proteins. Initiation of viral transcription is also an RNA independent process where host transcription promoters and enhancer elements such as NF-kB bind to the 5 -LTR. The host transcriptional complex is then recrnited and transcription commences.Once transcription has been initiated, RNA and RNA-RNA interactions play a critical role in mediating the production of viral transcripts. The multiprotein transcription complex has a recognition factor for nonhost DNA and quickly releases from viral DNA, creating short, abortive transcripts. Processing and nuclear export of these transcripts leads to the translation of the HIV Tat protein, a small early-phase viral protein (Figure 10.4) that plays a key role in the ultimate formation of fnll-length viral RNA transcripts. 

Heintzman, N.D. etal. (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genetics, 39, 311-318. 

Observations that the 5 end of the mutation domain is near the transcriptional promoter stimulated speculation that the initiation of transcription is in some way involved in the generation of mutations. Betz et al. (1994) showed that the two transcriptional enhancer elements in the K locus, one in the JC intron and the other 9 kb 3 to CK, are important for effective hypermutation. The intron enhancer appeared to be absolutely required, whereas deletion of the 3 enhancer reduced but did not abolish mutation. The promoter 5 of the VK transcription start site (Falkner and Zachau, 1984 Parslow et al., 1984) was replaced by the human P-globin promoter without deleterious effect on mutation, indicating that specific promoter elements may not be required. Heavy chain transgenes with a heterologous promoter can also undergo mutation (Tumas-Brundage and Manser, 1997). 

TGF-/31 was also evaluated with NOD mice for the prevention of autoimmune diabetes, since it down-regulates many immune responses (Piccirillo et al., 1998). In TGF-/31 expression plasmid, pCMV-TGF-/ 1, the mTGF-/31 cDNA is under the transcriptional control of a CMV promoter/enhancer. Intramuscular injection of the plasmid showed TGF-/51 mRNA expression in skeletal muscle cells, as well as an increased level of TGF-/31 in the plasma of treated mice. Administration of pCMV-TGF-gl / was effective in protecting NOD mice from insulitis and diabetes. In addition, there was a decreased expression of IL-12 and IFN7 mRNA in the pancreas of protected mice. 

In eukaryotic organisms, transcription regulation is a complex process that demands coordinated interaction of several genetic elements. The efficiency of this process mainly depends on the promoter/enhancer sequences, the copy number of the gene, and the structure and elements present at the insertion site in the host s chromatin. On the other hand, the co-transcriptional modifications (capping, splicing, polyadenylation, and transport to cytoplasm) on the primary transcript determine the stability, turnover rate, and translational capacity of the future mRNA. 

Enhancer DNA sequence that binds a transcription factor. Enhancers typically are not part of the proximal promoter and often are effective from a long distance, in either orientation, 5 or 3 to a gene. 

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