Why are genes regulated

However, two different cells of the same type may also have different gene expression patterns depending on their environment and internal state. Instead, they have molecular pathways that convert information—such as the binding of a chemical signal to its receptor—into a change in gene expression.

A growth factor is a chemical signal from a neighboring cell that instructs a target cell to grow and divide. This is just one example of how a cell can convert a source of information into a change in gene expression. There are many others, and understanding the logic of gene regulation is an area of ongoing research in biology today.

Growth factor signaling is complex and involves the activation of a variety of targets, including both transcription factors and non-transcription factor proteins. Alcohol dehydrogenase. Cooper, G. Regulation of transcription in eukaryotes. In The cell: A molecular approach. Sunderland, MA: Sinauer Associates. Kimball, John W. The human and chimpanzee genomes.

OpenStax College, Biology. Eukaryotic transcription gene regulation. Regulation of gene expression. Phillips, T. Regulation of transcription and gene expression in eukaryotes. Nature Education , 1 1 , Purves, W. Transcriptional regulation of gene expression. In Life: The science of biology 7th ed. Reece, J. Eukaryotic gene expression is regulated at many stages. In Campbell Biology 10th ed. How do genes direct the production of proteins?

What is epigenetics? How do cells divide? How do genes control the growth and division of cells? How do geneticists indicate the location of a gene? It is crucial for the proper development and function of an organism that only some of the genes in its genome are expressed at a certain time, under particular conditions, or in each specific cell type.

It is therefore fitting that a vast amount of research has been devoted to understanding how genes are regulated. A key control point in regulating expression is the initiation of transcription, and much is known about how the transcription machinery assembles near the site of initiation and starts transcribing Luse, ; Robinson et al. Even though the textbook description of gene regulation by general and regulatory transcription factors binding to conserved DNA sequences in promoters 1 and enhancers nicely explains the behavior of most genes, some observations are difficult to reconcile with the standard model.

One example is the surprisingly large effect that some introns have on gene expression. In fact, certain introns may be the primary element directing the expression of some of the most highly expressed genes in the genome, causing the gene to be constitutively activated like a car with a heavy brick on its accelerator. These introns reveal a broad gap in our understanding of gene expression, and could be powerful tools for maximizing protein production in biotechnological and therapeutic applications.

This article focuses on the specific kind of intron that increases mRNA accumulation because these introns seem to play a major role in regulating the gene in which they are located and because their effects are difficult to fit into our current understanding of gene expression. There are numerous other important ways in which introns increase gene expression through general effects of splicing or specific features of individual introns acting by known mechanisms, as detailed in other reviews Le Hir et al.

Multiple interconnections between the various machineries that carry out splicing, transcription, polyadenylation, mRNA export, and translation provide opportunities for synergistic interactions through which introns can help generate more gene product Maniatis and Reed, ; Dahan et al.

These effects should apply to all efficiently spliced introns more or less equally if they are processed by the same splicing machinery. In addition to these general effects, specific introns may contain one or more various features that boost expression, such as an enhancer element Kim et al. Other introns are known to have direct or indirect negative effects on gene expression Gromak, ; Jin et al.

Because most eukaryotic genomes contain thousands of introns, there are multiple opportunities for introns to affect expression in a host of different ways. An enormous amount of work will be required to sort out all the mechanisms through which introns affect expression and the evolutionary relationships between them. Much of the existing research on introns has been performed in plants, which are the focus of this article. One possible reason is the relatively large number and small size of plant introns, which facilitates gene construction as well as computational analyses of intron sequences.

Another is the ease of generating transgenic plants containing single-copy integrated genes, which matters because the observed effect of introns on gene expression is roughly an order of magnitude larger in stable transformants than it is when the same genes are used in transient expression assays Rollfinke et al. The phenomenon clearly is not limited to plants and the diverse range of organisms in which introns have been shown to elevate expression Okkema et al. Efficiently spliced introns vary widely in their effect on mRNA levels Rose, , indicating that the mechanism through which introns influence mRNA accumulation is not simply a function of splicing.

The main evidence that mRNA-increasing introns represent a new kind of regulatory element is that their properties are different from the characteristics of enhancers and promoters Zabidi and Stark, ; Medina-Rivera et al. Experiments in which the location of an expression-stimulating intron was varied in a gene revealed that the intron must be within transcribed sequences and less than 1 kb from the start of transcription to increase mRNA levels Rose, ; Gallegos and Rose, These introns are therefore unlike enhancer elements, which operate over long distances in both directions to activate transcription from a promoter Zabidi and Stark, They are also unlike promoters in that the introns must be downstream of the transcription start site to affect expression.

Deletion analysis, which has been used to locate important promoter and enhancer sequences, has proven largely ineffective in identifying the intron sequences responsible for increasing mRNA accumulation.

In at least the case of the Arabidopsis UBQ10 intron, this is because the active sequences are distributed throughout the stimulating intron rather than forming a single discrete element such as the binding site for a transcription factor Rose et al. The ability to predict which introns will increase mRNA accumulation, and to identify the intron sequences responsible for affecting expression, was greatly improved by the development of a computational tool known as the IMEter Rose et al.

This algorithm is based on the hypothesis that many introns throughout the genome might boost mRNA accumulation only when near the start of transcription, and as a result there may be detectable differences between promoter-proximal and promoter-distal introns caused by an increased abundance of IME-related sequences in promoter-proximal introns.

The composition of all the introns in both groups is determined by calculating the frequency of occurrence of all possible nucleotide words of a given length, such as pentamers.

A test sequence is then compared to these two k-mer profiles and a numerical score is generated, with a higher score reflecting a greater degree of similarity of that sequence to promoter-proximal introns. The algorithm works best for organisms with relatively small introns, and online versions are available for nearly three-dozen species of plants 2. Computational difficulties prevent the development of IMEters for organisms such as mammals with very large introns.

However, other approaches have begun to yield information about expression-stimulating sequences in human introns Cenik et al.

Figure 1. The function of the IMEter algorithm. The sequences of the introns in a genome are computationally separated into two groups based on whether the start of the intron is less than or greater than a threshold distance from the start of transcription for that gene.

For each population of intron sequences, the frequency of occurrence of all possible nucleotide words of a given length such as the pentamers shown is calculated. A test sequence is compared to those two profiles, generating a numerical score that reflects the degree to which that sequence more strongly resembles the profile of promoter-proximal introns.

Detailed descriptions of the underlying calculations, and the refinements added in different versions of the IMEter, can be found in Rose et al. It also allows the effect on expression of an intron to be predicted from its sequence alone. This in turn permits a broader analysis of the types of genes that contain introns likely to affect their expression, as well as the nature of the gene regulation that introns exert. Several lines of evidence indicate that introns drive a constitutive high level of expression in most or all tissues.

Genome-wide, genes containing introns with high IMEter scores are generally expressed in a greater number of plant organs than genes without a high-scoring intron Parra et al. This is in agreement with the kinds of genes in which stimulating introns historically have been discovered by comparing the expression of cDNA and genomic versions of the same gene.

While this represents a small sample rather than an exhaustive survey, and there are multiple exceptions, many of the genes that contain a stimulating intron encode proteins that are needed in large amounts in most cell types, such as ubiquitin Norris et al. Additional evidence that introns generally produce strong constitutive gene expression is that inserting an expression-stimulating intron into a gene that is normally active only in certain cell types can override the regulation provided by the promoter and result in widespread expression Jeong et al.

The presence of a stimulating intron need not necessarily always result in ubiquitous expression because additional kinds of regulation could be combined with intron-driven expression. For example, a gene that contains a stimulating intron might be highly transcribed in all tissues, but the presence of a miRNA could eliminate the mRNA in certain cells, resulting in differential accumulation of mRNA in various locations.

Another indication of the powerful effect introns can have on expression came unexpectedly from a study of the promoters of the most active genes in soybeans Zhang et al.

All of the genes identified as producing the highest amount of mRNA throughout the plant contain an intron with a high IMEter score 92nd percentile or higher near the start of the gene Figure 2. It depends what strings you push down and what strings you strum, or what keys are up and what keys are down, [that] determine what the profile of the gene expression will be or the sound that you hear.

Gene Regulation. David M. Bodine, Ph. Featured Content. Introduction to Genomics. Polygenic Risk Scores.