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David Sadava, David M. Hillis, H. Craig Heller, May R. Berenbaum La nuova biologia.blu Genetica, biologia molecolare ed evoluzione S Regulation of Gene Expression How Is Gene Expression Regulated in Prokaryotes? Prokaryotes can make some proteins only when they are needed. E. coli in the human intestine must adjust quickly to changes in food supply. Glucose is the easiest sugar to metabolize. If E.coli is grown with glucose but no lactose, no enzymes for lactose conversion are produced. If lactose is predominant and glucose is low, E.coli synthesizes all enzymes after a short lag period. How Is Gene Expression Regulated in Prokaryotes? Structural genes specify primary protein structure— the amino acid sequence. The 3 structural genes for lactose enzymes are adjacent on the chromosome and share a promoter, forming the lac operon. How Is Gene Expression Regulated in Prokaryotes? An operon is a gene cluster with a single promoter. A typical operon consists of: •a promoter •a terminator •an operator •Two or more structural genes An operator—a short sequence between the promoter and the structural genes; binds to regulatory proteins. How Is Gene Expression Regulated in Prokaryotes? Three ways to control operon transcription: • An inducible operon regulated by a repressor protein • A repressible operon regulated by a repressor protein • An operon regulated by an activator protein How Is Gene Expression Regulated in Prokaryotes? In the lac operon (inducible operon) the operator can bind a repressor protein, which blocks transcription. The repressor has 2 binding sites: one for the operator, and one for the inducer (lactose). When lactose is absent, the repressor prevents binding of RNA polymerase to the promoter. How Is Gene Expression Regulated in Prokaryotes? When lactose is present, it binds to the repressor and changes the repressor’s shape. This prevents the repressor from binding to the operator, and then RNA polymerase can bind to the promoter, and the genes are transcribed. How Is Gene Expression Regulated in Prokaryotes? The trp operon is a repressible system. In these systems, the repressor isn’t bound to the operator until a co-repressor binds to it. The genes code for enzymes that catalyze synthesis of tryptophan. When there is enough tryptophan in the cell, tryptophan binds to the repressor, which then binds to the operator. Tryptophan is the co-repressor. How Is Eukaryotic Gene Transcription Regulated? In development of multicellular organisms, certain proteins must be made at just the right times and in just the right cells. The expression of eukaryotic genes must be precisely regulated. Regulation can occur at several different points and the presence of a nucleus physically separates transcription and translation. Table 16.2 How Is Eukaryotic DNA Transcribed and the RNA Processed? RNA splicing removes introns and splices exons together. snRNPs (small nuclear ribonucleoprotein particles) bind to ends of introns at consensus sequences— short DNA stretches that appear in many genes. How Is Eukaryotic DNA Transcribed and the RNA Processed? If the initial mRNA transcript (precursor or premRNA) is hybridized with DNA, there is full, linear, loop-free hybridization. The intervening regions (introns) get transcribed then sliced out of pre-mRNA in the nucleus. Only expressed sequences (exons) reach the ribosome. How Is Eukaryotic DNA Transcribed and the RNA Processed? In the nucleus, pre-mRNA is modified: •A 5′ cap is added at the 5′ end— also protects mRNA from being digested by ribonucleases. •A poly A tail is added at 3′ end— the tail assists in export from the nucleus and is important for stability of mRNA. How Is Eukaryotic DNA Transcribed and the RNA Processed? Mature mRNA leaves the nucleus through nuclear pores. A cap-binding protein complex binds to the 5′ cap and to other proteins that are recognized by receptors at the nuclear pore. These proteins lead the mRNA through the pore; unused pre-mRNAs stay in the nucleus. How Do Epigenetic Changes Regulate Gene Expression? Patterns of DNA methylation may include large regions or whole chromosomes. Two kinds of chromatin: • Euchromatin—diffuse, light-staining; contains DNA that is transcribed • Heterochromatin—condensed, dark-staining, contains genes not transcribed How Do Epigenetic Changes Regulate Gene Expression? Chromosomal protein alterations or chromatin remodeling: DNA is packaged with histone proteins into nucleosomes. The DNA is inaccessible to RNA polymerase and transcription factors. The histones have “tails” with positively charged amino acids, which are attracted to negatively charged DNA. How Do Epigenetic Changes Regulate Gene Expression? One type of heterochromatin is the inactive X chromosome in mammals. Males (XY) and females (XX) contain different numbers of X-linked genes, yet for most genes transcription rates are similar. Early in development, one of the X chromosomes in females is inactivated. How Is Eukaryotic Gene Transcription Regulated? Promoters bind and orient RNA polymerase so that the correct DNA strand is transcribed. All promoters have consensus sequences that allow them to be recognized by RNA polymerase. Eukaryote promoters contain a sequence called the TATA box—where DNA begins to denature. Promoters also include regulatory sequences recognized by transcription factors (regulatory proteins). How Is Eukaryotic Gene Transcription Regulated? Some regulatory sequences are common to promoters of many genes, other sequences are specific to a few genes and are recognized by transcription factors found only in certain tissues. These play an important role in cell differentiation. Enhancers: regulatory sequences that bind transcription factors that activate transcription or increase rate of transcription. Silencers: bind transcription factors that repress transcription. How Is Eukaryotic Gene Transcription Regulated? Most regulatory sequences are located near the transcription start site. Others may be located thousands of base pairs away. Transcription factors may interact with the RNA polymerase complex and cause the DNA to bend. How Is Eukaryotic Gene Transcription Regulated? Often there are many transcription factors involved. The combination of factors present determines the rate of transcription. Although the same genes are present in all cells, the fate of the cell is determined by which of its genes are expressed. How Is Eukaryotic Gene Transcription Regulated? Cellular therapy is a new approach to diseases that involve degeneration of one cell type. Alzheimer’s disease involves degeneration of neurons in the brain. If other cells could be made to differentiate into neurons, they could be transferred to the patient. How Is Eukaryotic Gene Expression Regulated After Transcription? Alternative splicing: different mRNAs can be made from the same gene. Introns are spliced out; mature mRNAs have none. Sometimes exons are spliced out too—resulting in different proteins. There are many more human mRNAs than there are coding genes. How Is Eukaryotic Gene Expression Regulated After Transcription? MicroRNAs(miRNAs): small RNAs produced by noncoding regions of DNA. The human genome has about 1,000 miRNA encoding regions. How Is Eukaryotic Gene Expression Regulated After Transcription? Protein longevity regulation: Proteins can be targeted for destruction when ubiquitin attaches to it and attracts other ubiquitins, forming a polyubiquitin chain. The complex binds to a proteasome—a large complex where the ubiquitin is removed and the protein is digested by proteases. How Is Eukaryotic Gene Expression Regulated After Transcription? Some strains of human papillomavirus (HPV) add ubiquitin to p53 and retinoblastoma proteins, targeting them for degradation. These proteins normally inhibit the cell cycle, so the result of this HPV activity is unregulated cell division (cancer). What Are the Processes of Development? Development: the process in which a multicellular organism undergoes a series of progressive changes that characterizes its life cycle. In its earliest stages, a plant or animal is called an embryo. What Are the Processes of Development? Four processes of development: • Determination sets the fate of the cell • Differentiation—the process by which different types of cells arise • Morphogenesis—organization and spatial distribution of differentiated cells • Growth—increase in body size by cell division and cell expansion How Does Gene Expression Determine Pattern Formation? Fate of a cell is often determined by where the cell is. Positional information often comes in the form of an inducer called a morphogen, which diffuses from one group of cells to another, setting up a concentration gradient. How Does Gene Expression Determine Pattern Formation? Morphogens have been studied in the fruit fly Drosophila melanogaster. The head, thorax, and abdomen are each made of several fused segments. In the first 12 mitotic divisions there is no cytokinesis, forming a multinucleate embryo. Morphogens can diffuse easily in the embryo. How Does Gene Expression Determine Pattern Formation? The experiments revealed a cascade of gene expression. Three gene classes are involved: 1. Maternal effect genes set up the major axes of the egg. Bicoid and nanos help determine the anterior– posterior axis of the embryo. How Does Gene Expression Determine Pattern Formation? 2. Segmentation genes determine boundaries and polarity of each segment. Three classes of genes act in sequence: • Gap genes organize broad areas; • Pair rule genes divide embryo into units of two segments each; • Segment polarity genes determine boundaries and anterior–posterior organization in individual segments. How Does Gene Expression Determine Pattern Formation? 3. Hox genes determine which organ will be made at a given location. They determine cell fate in each segment. Hox genes are on chromosome 3 in the same order as the segments whose functions they determine. Antennapedia mutation Bithorax mutation How Does Gene Expression Determine Pattern Formation? Hox genes have a 180 base pair sequence called the homeobox. It encodes a 60 amino acid sequence called the homeodomain. The homeodomain binds to specific DNA sequences in the promoters of target genes. This homeodomain is found in transcription factors that regulate development in many other animals with an anterior–posterior axis. How Does Gene Expression Determine Pattern Formation? Pattern formation: The process that results in the spatial organization of tissues and organisms. Linked to morphogenesis, creation of body form. Morphogenesis involves cell division and differentiation, as well as apoptosis (programmed cell death). In human embryos, connective tissue links the fingers and toes. Later, the cells between the digits die. Adapted from Life: The Science of Biology, Tenth Edition, Sinauer Associates, Sunderland, MA, 2014 Inc. All rights reserved