Chapter 18 - Regulation of Gene Expression Flashcards
How do bacteria respond to environmental changes?
By regulating transcription; natural selection has favored bacteria that produce only the products needed by that cell
A cell can regulate the production of enzymes by feedback inhibition or by gene regulation; one mechanism for control of gene expression in bacteria is the operon model
What is an operator?
A cluster of functionally related genes can be controlled by a single “on-off switch”; the “switch” is a segment of DNA called an operator, usually positioned within the promoter
The operator controls the access of RNA polymerase to the genes
What is an operon?
Altogether, the operator (on off switch), the promoter (the places where RNA polymerase binds), and the genes they control, constitute an operon
- By default, the trp operon is on and the genes for tryptophan synthesis are transcribed
- When tryptophan is present, it binds to the trp repressor protein, which turns the operon off
What is the repressor?
The operon can be switched off by a protein that is called the trp repressor; the repressor prevents gene transcription by binding to the operator and blocking RNA polymerase
A repressor protein is specific for the operator of a particular operon
The repressor can be in an active or inactive form, depending on the presence of other molecules;
The repressor is active only in the presence of its corepressor tryptophan; thus the trp operon is turned off if tryptophan levels are high
What is the regulatory gene?
The trp repressor is the protein product of a regulatory gene called trpR, which is located some distance from the trp operon and has its own promoter; regulatory genes are expressed continuously, although at a low rate
What is a corepressor?
A small molecule that cooperates with a repressor protein to switch an operon off
i.e. E. coli can synthesize the amino acid tryptophan when it has insufficient tryptophan
What is a repressible operon?
One that is usually on but can be inhibited when the binding of a repressor to the operator shuts off transcription
The trp operon is a repressible operon
What is an inducible operon?
Usually off but can be stimulated when a molecule called an inducer inactivates the repressor and turns on transcription
The lac operon in an inducible operon and contains genes that code for enzymes used in the hydrolysis and metabolism of lactose
What is an inducer?
A specific small molecule that inactivates the repressor (to turn the lac operon on)
What are inducible enzymes?
Inducible enzymes usually function in catabolic pathways; their synthesis is induced by a chemical signal
What are repressible enzymes?
Repressible enzymes function in anabolic pathways; their synthesis is repressed by high levels of the end product
What is an activator?
A protein that binds to DNA and stimulates transcription of a gene
Some operons are subject to positive control through a stimulatory protein, such as catabolite activator protein (CAP); when glucose (preferred food source of E. coli) is scarce, CAP is activated by binding with cyclic AMP (cAMP); activated CAP attached to the promotor of the lac operon and increases the affinity of RNA polymerase, thus accelerating transcription; when glucose levels decrease, CAP detaches from the lac operon, and transcription returns to a normal rate — CAP helps regulate other operons that encode enzymes used in catabolic pathways
What is differential gene expression?
The expression of different genes by cells with the same genome, giving rise to differences between cell types
- Almost all cells in an organism are genetically identical
- Abnormalities in gene expression can lead to cancer
Discuss the regulation of chromatin structure.
- The structural organization of chromatin helps regulate gene expression in several ways
- Genes within highly packed heterochromatin are usually not expressed
- Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression
What is histone acetylation?
Acetyl groups (-COCH3) are attached to positively charged lysines in histone tails; this looses the chromatin structure, thereby promoting the initiation of transcription
*The addition of methyl groups (methylation) can condense chromatin; the addition of phosphate groups (phosphorylation) next to a methylated amino acid can loose chromatin
What is DNA methylation?
The addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species; can cause long term inactivation of genes in cellular differentiation
*In genomic imprinting, methylation regulations expression of either the maternal or paternal alleles of certain genes at the start of development
What is epigenetic inheritance?
Inheritance of traits transmitted by mechanisms not involving the nucleotide sequence itself
What are control elements?
Associated with most eukaryotic genes; segments of noncoding DNA that serve as binding sites for the proteins called transcription factors, which in turn regulate transcription
Control elements and the transcription factors they bind are critical to the precise regulation of gene expression in different cell types
What does eukaryotic RNA polymerase require to initiate transcription?
The assistance of transcription factors
What are general transcription factors?
Essential for the transcription of all protein-coding genes
What are enhancers?
Distal control elements, groupings of which are called enhancers, may be far away from a gene or even located in an intron
*The rate of gene expression can be strongly increased or decreased by the binding of specific transcription factors, either activators or repressors, to the control elements of enhancers
In more detail, what is an activator?
A protein that binds to an enhancer and stimulates the transcription of a gene
Activators have two domains, one that binds DNA and a second that activates transcription; bound activators facilitate a sequence of protein-protein interactions that result in transcription of a given gene
What can sometimes function as a repressor, inhibiting expression of a particular gene?
Some transcription factors function as repressors; some activators and repressors act indirectly by influencing chromatin structure to promote or silence transcription
What is alternative RNA splicing?
In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns
Discuss “Initiation of Translation and mRNA Degradation”
The initiation of translation of selected mRNAs can be blocked by regulatory proteins that bind to sequences or structures of the mRNA
Alternatively, translation of all mRNAs in a cell may be regulated simultaneously
For example, translation initiation factors are simultaneously activated in an egg following fertilization
The life span of mRNA molecules in the cytoplasm is a key to determining protein synthesis
Eukaryotic mRNA is more long lived than prokaryotic mRNA
Nucleotide sequences that influence the lifespan of mRNA in eukaryotes reside in the untranslated region (UTR) at the 3′ end of the molecule
Discuss “Protein Processing and Degradation”.
After translation, various types of protein processing, including cleavage and the addition of chemical groups, are subject to control
The length of time each protein function is regulated by selective degradation
Cells mark proteins for degradation by attaching ubiquitin to them
This mark is recognized by proteasomes, which recognize and degrade the proteins
Discuss how noncoding RNAs play multiple roles in controlling gene expression.
ncRNAs; Only a small fraction of DNA codes for proteins, and a very small fraction of the non-protein-coding DNA consists of genes for RNA such as rRNAand tRNA
A significant amount of the genome may be transcribed into noncoding RNAs (ncRNAs)
Noncoding RNAs regulate gene expression at two points: mRNA translation and chromatin configuration
ncRNAs are responsible for X chromosome inactivation, which, in most female mammals, prevents expression of genes located on one of the X chromosomes
What are microRNAs?
miRNAs; capable of binding to complementary sequences in mRNA molecules
A single stranded RNA of about 22 nucleotides that forms a complex with one or more proteins; the miRNA allows the complex to bind to any mRNA molecule with at least 7 or 8 nucleotides of complementary sequence
The miRNA complex then either degrades the target mRNA or blocks its translation
It is estimated that expression of at least half of all human genes may be regulated by miRNAs
What are small interfering RNAs?
siRNAS; similar to miRNAs in size and function, associating with similar proteins and producing similar results
Turn of expression of genes with related sequences
What is RNA interference?
RNAi; the blocking of gene expression by siRNAs; used in the laboratory as a means of disabling specific genes to investigate their function
What are piRNAs?
Piwi-interacting RNAs (piRNAs); a newly discovered class of small ncRNAS that induce formation of heterochromatin, blocking expression of some parasitic DNA elements in the genome known as transposons
What is differentiation?
The process by which cells become specialized in structure and function
The process by which a cell attains its determined fate
Differentiated cells are specialists at making tissue specific proteins
What is morphogenesis?
The physical processes that give an organism its shape constitute morphogenesis, the development of the form of an organism and its structures
What is the three step program of differential gene expression that leads to a multicellular organism?
- Cell division
- Cell differentiation
- Morphogenesis
Materials placed into the egg by the mother set up a sequential program of gene regulation that is carried out as cells divide, and this program coordinates cell differentiation during embryonic development
What are cytoplasmic determinants?
Maternal substances in the egg that influence the course of early development; after fertilization, early mitotic divisions distribute the zygote’s cytoplasm into separate cells; the nuclei of these cells may thus be exposed to different cytoplasmic determinants, depending on which portions of the zygotic cytoplasm a cell received
The combination of cytoplasmic determinants in a cell helps determine its developmental fate by regulating expression of the cell’s genes during he course of cell differentiation
What is induction?
Most influential are the signals impinging on an embryonic cell from other embryonic cells in the vicinity, including contact with cell-surface molecules on neighboring cells and the binding of growth factors secreted by neighboring cells
Such signals cause changes in the target cells, a process called induction
The molecules conveying these signals within the target cell are cell surface receptors and other signaling pathways proteins
The signaling molecules send a cell down a specific developmental path by causing changes in its gene expression that eventually result in observable cellular changes
What is determination?
Refers to the point at which an embryonic cell is irreversibly committed to becoming a particular cell type
Once a cell has undergone determination, an embryonic cell can be experimentally placed in another location in the embryo and it will still differentiate into the cell type that is its normal fate
What is myoD?
A master regulatory gene; this gene encodes MyoD protein, a transcription factor that binds to specific control elements in the enhancers of various target genes and stimulates their expression
What is the body plan?
The organism’s overall three dimensional arrangement; must be established and super imposed on the differentiation process
What is pattern formation?
Cytoplasmic determinants and inductive signals both contribute to the development of a spatial organization in which the tissues and organs of an organism are all in their characteristic places
What is positional information?
The molecular cues that control pattern formation; provided by cytoplasmic determinants and inductive signals; these cues tell a cell its location relative to the body axes and to neighboring cells and determine how the cell and its progeny will respond to future molecular signals
What are homeotic genes?
Control pattern formation in the late embryo, larva, and adult
What are embryonic lethals?
Mutations with phenotypes causing death at the embryonic or larval stage
What is a maternal effect gene?
A gene that, when mutant in the mothers, results in a mutant phenotype in the offspring, regardless of the offspring’s own genotype
Also called egg polarity genes; one group of these genes sets up the anterior posterior axis of the embryo, while a second group establishes the dorsal ventral axis
*Mutations in maternal effect genes are generally embryonic lethals
What are morphogens?
The morphogen gradient hypothesis is where gradients of substances called morphogens establish and embryo’s axes and other features of its form
What does cancer result from?
Genetic changes that affect cell cycle control; cancer can be caused by mutations to genes that regulate cell growth and division and mutations in the genes can be caused by spontaneous mutations or environmental influences such as chemicals, radiation, and some viruses
The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development
What are oncogenes?
Cancer causing genes in certain types of viruses
What are proto-oncogenes?
The normal versions of the cellular genes that code for proteins that stimulate normal cell growth and division
How might a proto-oncogene become an oncogene?
An oncogene arises from a genetic change that leads to an increase either in the amount of the proto-oncogene’s protein product or in the intrinsic activity of each protein molecule. The genetic changes that convert proto-oncogenes to oncogenes fall into three main categories;
- Translocation or transposition - movement of DNA within the genome; gene moved to new locus, and under new controls (normal growth stimulating protein in excess)
- Gene amplification - amplification of a proto-oncogene (multiple copies) (normal growth stimulating protein in excess)
- Point mutation - point mutations in a control element or in the proto-oncogene itself; cause an increase in gene expression (normal growth stimulating protein in excess) (hyperactive or degradation resistant protein)
What are tumor suppressor genes?
Inhibit cell division; the proteins they encode help prevent uncontrolled cell growth
Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset
What are three functions of tumor-suppressor proteins?
Repair damaged DNA
Control cell adhesion
Act in cell-signaling pathways that inhibit the cell cycle
What mutations on what genes are common in human cancer?
Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers
What is the ras gene?
A G protein that relays a signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases; the cellular response at the end of the pathway is the synthesis of a protein that stimulates the cell cycle
Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division
What is the p53 gene?
A tumor-suppressor gene; the protein it encodes is a specific transcription factor that promotes the synthesis of cell cycle inhibiting proteins (prevents a cell from passing on mutations due to DNA damage)
- Activates expression of a group of miRNAs, which in turn inhibit the cell cycle
- Can turn on genes directly involved in DNA repair
- When DNA damage is irreparable, p52 activates “suicide” genes, whose protein products bring about programmed cell death (apoptosis)
A mutation that knocks out the p53 gene, can lead to excessive cell growth and cancer
*The guardian angel of the genome
Discuss the multistep model of cancer development.
- Multiple mutations are generally needed for full-fledged cancer; thus the incidence increases with age
- At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes
- Breast cancer is a heterogeneous disease that is the commonest form of cancer in women in the United States
- A genomics approach to profiling breast tumors has identified four major types of breast cancer
Discuss inherited predisposition and environmental factors contributing to cancer.
- Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes
- Inherited mutations in the tumor-suppressor gene adenomatous polyposis coliare common in individuals with colorectal cancer
- Mutations in the BRCA1or BRCA2gene are found in at least half of inherited breast cancers, and tests using DNA sequencing can detect these mutations
Discuss the role of viruses in cancer.
- A number of tumor viruses can also cause cancer in humans and animals
- Viruses can interfere with normal gene regulation in several ways if they integrate into the DNA ofa cell
- Viruses are powerful biological agents
What is heterochromatin?
Eukaryotic chromatin that remains highly compacted during interphase and is generally not transcribed
What is euchromatin?
The less condensed form of eukaryotic chromatin that is available for transcription
