Gene expression and regulation

A gene is a section of DNA that is transcribed into RNA which in turn encodes a protein (although a small number of unusual genes are not translated and indeed cannot be translated into protein). For reasons that are still unclear, large portions of transcribed RNA are excised (by RNA splicing enzymes) and additional modifications are made to the ends of the RNA molecule (capping of one end and polyadenylation of the other). The final product, messenger RNA ( mRNA), contains a central section, translated into protein, and flanking non-coding regions. The consequence of these manipulations is that DNA and mRNA are not coterminous; sections of DNA that encode mRNA (termed exons) are interrupted by often very large stretches of DNA that are not translated (termed introns) ( Fig 1).

Fig. 1 The figure shows the process of transcription by which mRNA is produced from DNA. At the top of the figure the organization of a gene in genomic DNA is shown. Unshaded boxes correspond to coding regions (exons) and the two shaded boxes correspond to control regions. The control region immediately 5' of the first exon, where transcription is initiated, is known as the promoter and often has a characteristic sequence composition. In almost all ubiquitously expressed genes (and in many tissue-specific genes) it is unmethylated, GC rich, and has a relative excess of the dinucleotide CpG. The region, which typically contains the first exon as well as the promoter, is called a CpG island. The boundaries between exons and introns are called splice sites and are conserved; introns virtually always start with the sequence GT and end with the sequence AG. The entire genomic region is transcribed into a primary transcript (bold arrow) which is then processed to excise the introns. Many human genes undergo alternative splicing to yield a number of different mRNA products. Mature mRNA is then translated into a protein product.

We know of a number of ways in which gene expression is controlled. Predominantly it occurs at the level of transcription (but post-transcriptional processing and translational control are important for some genes). Transcriptional control involves at least three mechanisms, which are illustrated in Fig;..,.?.

Fig. 2 Factors involved in regulating the transcription of DNA. Gene expression requires an RNA polymerase which initially binds to the 5' end of the gene at the promoter. The figure shows polymerization occurring once transcription factors have bound to DNA and to the polymerase. Note that the transcription factors are binding not only close to the gene, but also at a distance. Transcription occurs in the centre of the figure, in a region of DNA devoid of chromatin. Shaded ovals indicate nucleosomes, one level at which chromatin packages DNA. The higher-order structure of chromatin is unknown, but is indicated on the right of the figure by tightly packed nucleosomes.

First, transcription factors exercise control over gene expression. Transcription occurs when RNA polymerases manufacture RNA from the template DNA, a process that requires the help of transcription factors, proteins that recognize and bind to specific DNA sequences (note that transcription factors can also repress transcription). Although transcription factor binding sites are found close to a gene, at a 5' region known as the promoter (see Fig 1), they may also be situated far away, sometimes within other genes. Transcription factors are themselves the products of genes, so that they may control their own expression or be part of more complex sets of interacting regulatory pathways.

Second, transcription can be controlled by the extent to which the DNA is made accessible to the transcriptional machinery. DNA does not exist in a free state in the cell; it is closely associated with a complex of proteins called chromatin. For a long time chromatin was considered to be merely a way of packing DNA into the nucleus, but it is now clear that it is intricately involved in DNA metabolism. Figure,? shows how DNA is wrapped around nucleosomes, which are composed of chromatin proteins. On the right the nucleosomes are packed together and, although the higher-order structure is not known, tightly packed nucleosomes mean that DNA cannot be transcribed. DNA has to be free of nucleosomes for it to be accessible to transcription factors and the large complex of proteins that constitutes RNA polymerase. Actively transcribed DNA lies in regions of relatively open chromatin, which can be experimentally identified by their accessibility to enzymes that digest DNA (nucleases). Therefore understanding what controls chromatin packaging will reveal one way of controlling gene expression. For this reason there has been much interest in characterizing proteins that remodel chromatin and consequently influence many biochemical pathways, including the control of genes involved in the development and activity of the central nervous system. For example, the mental retardation syndrome ATRX (discussed below) is due to a mutation in a transcriptional regulator that probably acts by remodelling chromatin.(6)

Gene expression can also be altered by the addition of methyl groups to cytosine bases. Methylation of DNA does not change the DNA sequence but, when it affects control regions, is associated with gene inactivation. It is not clear whether methylation is an independent mechanism for regulating gene expression, since methylation directs chromatin into an inactive conformation, mediated by methylated DNA binding proteins. Changes in methylation are involved in at least two mental retardation syndromes (the Prader-Willi and Angelman syndromes, discussed below).

Beat Depression Today

Beat Depression Today

I know this is hard for you to believe. I mean, to be able to be totally free of depression in such little time... and without any effort... not to mention the freedom to live your life, appear hard to fulfill at first glance... That is until you know the facts On a subconscious level, you will experience an incredible and exclusive Tri- Enhanced trance state of hypnosis to reprogram your mind to free you from negatize emotions.

Get My Free Ebook


Post a comment