Chap 18 Regulation of Gene Expression

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Chromatin modification: histone acetylation. Enzymes can add negative acetyl groups (—COCH3) to positively charged lysines in histone tails. This process loosens chromatin structure, making the DNA accessible to transcription. Such chromatin modifications may be passed to future generations of cells in a process called epigenetic inheritance.

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Activator proteins bind to distal control elements grouped as an enhancer in the DNA. A DNA-bending protein brings the bound activators closer to the promoter. The activators bind to transcription factors and mediator proteins, forming a transcription initiation complex on the promoter with RNA polymerase. Other transcription factors function as repressors.

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Gradients of bicoid mRNA and bicoid protein in egg and early embryo leads to normal development of the head.
Continue

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A lethal mutation in the mother’s bicoid gene leads to tail structures at both ends in the Drosophila mutant embryo.

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Mutations affecting tumor–suppressor genes (such as p53) may lead to benign growth in the colon lining called a polyp.

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Mutations in other tumor–suppressor genes and development of oncogenes can cause enlargement of the benign growth into an adenoma. Next

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Continured accumulation of mutations can culminate in the development of full-fledged cancer. This malignant tumor is called a carcinoma.

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A multistep model for the development of colorectal cancer. Affecting the colon and/or rectum, this type of cancer is one of the best understood. Next

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Transcription control. Distal control elements (far from the promoter, where RNA polymerase binds,) can be grouped together as enhancers and may interact with activators or repressors to control initiation of transcription.

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Cytoplasmic determinants. Uneven distribution of determinants, such as RNA, proteins, and organelles, in the cytoplasm of the unfertilized egg affect expression of genes and ultimately the cell’s developmental fate.

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Cytoplasmic determinants such as mRNA establish the axes of the body in Drosophila. Asymmetrically distribution of these molecules in the unfertilized egg eventually lead to differentiation of specialized segments of the adult. One important egg-polarity gene that encodes for such mRNA is the bicoid gene.

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Cell determination. MyoD is a “master regulatory gene” that produce proteins that commit the cell to becoming skeletal muscle. If a myoblast cell produces the MyoD protein (a transcription factor), it binds to enhancers of many target genes. The cell is now determined to be a skeletal muscle cell.

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Differences between cells is mainly due to differential gene expression, even though different cells share genomic equivalence.

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In the cytoplasm, regulation can occur by


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Regulation of eukaryotic gene expression may take place at different stages. In the nucleus, regulation can occur by

Cytoplasm

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The control elements can activate transcription only when the appropriate activator proteins are present. The particular combination of control elements and activator proteins enables a liver cell to express the albumin gene, while a lens cell expresses the crystallin gene.

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Mutations in homeotic genes cause a misplacement of structures in an animal.
An homeotic mutant Drosophila bears a pair of legs in place of antennae.

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Induction by nearby cells. The cells at the bottom of this early embryo release chemicals that signal nearby cells to change their gene expression (transcription).

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Lactose present, glucose scarce (cAMP level high): lac transcription stimulated.
RNA polymerase has high affinity for the lac promoter only when the activator, catabolite-activating protein (CAP), is bound next to the promoter.
CAP is active only when associated with cyclic AMP (cAMP), whose concentration in the cell rises when the concentration of the preferred glucose falls.

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Lactose present, glucose abundant (cAMP level low): lac transcription reduced.
When glucose levels increase, cAMP levels drop, and the catabolite-activating protein (CAP) is inactive.
The cell preferentially catabolizes glucose and does not make the lactose–utilizing enzymes.

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Lactose present, repressor inactive, operon on.
Allolactose, an isomer of lactose, serves as an inducer and derepresses the operon by inactivating the repressor, turning on transcription and translation of enzymes for lactose digestion.

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Lactose absent, repressor active, operon off.
E. coli uses 3 enzymes to take up and metabolize the sugar lactose. The genes for these 3 enzymes are clustered in the lac operon. In the absence of lactose, a repressor switches off the operon by binding to the operator.

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mRNA degradation.

  1. Single-stranded microRNAs (miRNAs) are noncoding RNAs that can form hairpin loops by hydrogen bonding.
  2. These are cut by the Dicer and can degrade complementary mRNA or block its translation.

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Morphogenesis encompasses the processes that give shape to the organism and its parts. It takes just one week for cell division, differentiation, and morphogenesis to transform a fertilized frog egg into a hatching tadpole.

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The p53 tumor suppressor gene encodes a transcription factor that regulates transcription of more than 50 different genes involved in the cell cycle. Cells with mutant p53 are unable to arrest at cell cycle checkpoints and become cancerous. _Vid_Discover2e/ch11a04_p53-tumor-suppressor.swf

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Protein degradation.
Unneeded proteins can be tagged with the protein ubiquitin.
The tagged protein is then chopped up by a proteasome.

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Proto-oncogenes are normal genes involved in cell growth and division. Mutations to a proto-oncogene can lead it to become a cancer-causing oncogene by producing growth-stimulating proteins that are in excess levels or that are hyperactive or degradation- resistant .

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RNA processing: alternative RNA splicing. The primary transcripts of some genes can be spliced in more than one way, generating different mRNA molecules. In this example one mRNA molecule has ended up with the green exon and the other with the purple exon. With alternative splicing, an organism can produce more than one type of polypeptide from a single gene.

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Tryptophan absent, repressor inactive, operon on.
In the repressible trp operon, 5 genes encoding the enzymes to synthesize tryptophan (an amino acid) are regulated by a promoter and an operator. When tryptophan is absent, the repressor (controlled by its own promoter) is inactive and the operon is on. RNA polymerase attaches to the DNA at the promoter and transcribes the operon’s genes.

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An operon is a group of functionally related genes under the control by a single on-off “switch” called an operator which is usually located within the promoter. Enzyme activity can be controlled by

  1. feedback inhibition when the product of the metabolic pathway depresses activity of the first enzyme in the pathway.
  2. gene regulation when the genes coding for the enzyme are not transcribed.

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Tryptophan present, repressor active, operon off.
The presence of tryptophan (a corepressor) activates the repressor which binds to the operator to turn the operon off by inhibiting the transcription of these genes by RNA polymerase.