Gene Expression in Eukaryotes

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University of Massachusetts Amherst
Mark Huyler

Gene Expression in Eukaryotes Key Concepts  Changes in gene expression allow eukaryotic cells to respond to changes in the environment and cause distinct cell types to develop.  Eukaryotic DNA is packaged with proteins into structures that must be opened before transcription can occur.  In eukaryotes, transcription is triggered by regulatory proteins that bind to the promoter and to sequences close to and far from the promoter.  Once transcription is complete, gene expression is controlled by:  Alternative splicing, which allows a single gene to code for several different products.  Molecules that regulate the life span of mRNAs.  Activation or inactivation of protein products.  Cancer can develop when mutations disable genes that regulate cell-cycle control genes. Introduction  The regulation of gene expression is more complex in eukaryotes than in prokaryotes.  Differential gene expression is responsible for creating different cell types, arranging them into tissues, and coordinating their activity to form the multicellular society we call an individual. Mechanisms of Gene Regulation—An Overview  Like prokaryotes, eukaryotes can control gene expression at the levels of transcription, translation, and post-translation.  Three additional levels of control are unique to eukaryotes:  Chromatin remodeling.  RNA processing.  Regulation of mRNA life span or stability. Chromatin Remodeling  In eukaryotes, DNA is wrapped around proteins to create a protein-DNA complex called chromatin.  RNA polymerase cannot access the DNA when it is supercoiled within the nucleus.  The DNA near the promoter must be released from tight interactions with proteins before transcription can begin; this process is called chromatin remodeling. RNA Processing and Control of mRNA Stability  Transcription results in a ―Primary RNA transcript‖ that must undergo RNA processing to produce a mature mRNA.  mRNA stability, or the life span of the mRNA, can also be used to control gene expression. What Is Chromatin’s Basic Structure?  Chromatin has a regular structure with several layers of organization.  Chromatin contains nucleosomes—repeating, beadlike structures.  Nucleosomes consist of negatively charged DNA wrapped twice around eight positively charged histone proteins.  A histone protein called H1 functions to maintain the structure of each nucleosome.  Between each pair of nucleosomes there is a ―linker‖ stretch of DNA.  H1 histones also may interact with each other and with histones in other nucleosomes to form a tightly packed structure called a 30-nanometer fiber.  These 30-nanometer fibers in turn may form higher- order structures.  Chromatin’s elaborate structure not only allows the DNA to be packaged in the nucleus, it also plays a key role in regulating gene expression. Chromatin Structure Is Altered in Active Genes  As in bacteria, eukaryotic DNA has sites called promoters where RNA polymerase binds to initiate transcription.  Studies support the idea that chromatin must be relaxed or decondensed for RNA polymerase to bind to the promoter. “Closed” or condensed DNA Is Protected from DNase  DNase is an enzyme that cuts DNA at random locations.  The enzyme cannot cut DNA when it is tightly complexed with histones. How Is Chromatin Altered?  Two major types of protein are involved in modifying chromatin structure:  ATP-dependent chromatin-remodeling complexes reshape chromatin.  Other enzymes catalyze the acetylation (addition of acetyl groups CH 3OO- and methylation (addition of methyl groups CH -3 of histones.  Acetylation of histones is usually associated with activation of genes. Methylation can be correlated with either activation or inactivation  One type of acetylation enzyme is called histone acetyl transferases (HATs). They add negatively charged acetyl groups to the positively charged lysine residues in histones.  This acetylation reduces the positive charge on the histones, decondensing the chromatin and allowing gene expression.  Enzymes called histone deacetylases (HDACs) then remove the acetyl groups from histones. This reverses the effects of acetylation and allows chromatin condensation. Chromatin Modifications Can Be Inherited  The pattern of chemical modifications on histones varies from one cell type to another.  The histone code hypothesis contends that precise patterns of chemical modifications of histones contain information that influences whether or not a particular gene is expressed.  Daughter cells inherit patterns of histone modification, and thus patterns of gene expression, from the parent cells.  This is an example of epigenetic inheritance, patterns of inheritance that are not due to differences in gene sequences. Imagine you’ve isolated a yeast mutant that contains histones resistant to acetylation. What phenotype do you predict for this mutant? a. The mutant will grow rapidly b. The mutant will show generally low levels of gene expression. c. The mutant will show generally high levels of gene expression d. The mutant will show low levels of gene expression for only a few select genes Regulatory Sequences and Regulatory Proteins  Eukaryotic promoters are similar to bacterial promoters. There are three conserved sequences and each eukaryotic promoter has two of the three.  The most common sequence is the TATA box.  All eukaryotic promoters are bound by the TATA- binding protein (TBP). Some Regulatory Sequences Are Near the Promoter  Regulatory sequences are sections of DNA that are involved in controlling the activity of genes. When regulatory proteins bind these sequences, they cause gene activity to change.  Some eukaryotic regulatory sequences are similar to those in bacteria, others are very different.  Yeast metabolize the sugar galactose. In the presence of galactose, transcription of the five galactose-utilization genes increases dramatically.  Mutant cells fail to produce any of the enzymes required for galactose metabolism, leading to three hypotheses:  The five genes are regulated together even though they are on different chromosomes.  Normal cells have a CAP-like regulatory protein that exerts positive control over the five genes.  The mutant cells have a loss-of-function mutation that completely disables the regulatory protein.  Promoter-proximal elements are located just upstream of the promoter and the transcription start site, and have sequences that are unique to specific genes, providing a mechanism for eukaryotic cells to exert precise control over transcription. Some Regulatory Sequences Are Far from the Promoter  While exploring how human immune system cells regulate genes that produce antibodies, Susumu Tonegawa and colleagues discovered that the intron, rather than the exon, contains a regulatory sequence required for transcription to occur.  The results were remarkable because:  The regulatory sequence was far from the promoter.  The regulatory sequence was downstream, rather than upstream, from the promoter.  Regulatory elements that are far from the promoter are termed enhancers. Characteristic
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