Regulation of Gene Expression

Regulation of Gene Expression

• Eukaryotes and prokaryotes regulate gene expression precisely based on the environment of the cell
• Gene expression is regulated in multicellular eukaryotes during development, which accounts for difference cell types within one organism.
• RNA molecules have roles in regulation gene expression in eukaryotes

Bacteria Response

• Bacteria respond to environmental change by regulating transcription
• Bacteria that produce only gene products that they actually need are favored by natural selection
• Cells regulate enzyme production in multiple ways including gene regulation and feedback inhibition
• Gene expression control in bacteria may use the operon model

Operons

• Functionally related genes are controlled coordinately through an 'on-off' switch
• Operators are segments of DNA which are switches
• An operon includes the operator, promoter, and genes they control
• The operon can be switched off by a repressor protein
• The repressor prevents gene transcription through binding to the operator, blocking RNA polymerase
• The repressor are coded by regulatory genes
• Regulatory genes are located some distance from the operon itself
• Repressors can be active or inactive - this depends on what other molecules are present
• Corepressors are molecules that will cooperate with a repressor protein to switch off the operon
• E. coli synthesizes tryptophan if there is not enough tryptophan present already, for example

The trp Operon

• The trp operon is on by default, therefore the genes for tryptophan are transcribed
• If tryptophan is present, then it binds to the trp repressor which turns the operon off
• High levels of tryptophan will switch off the trp operon because the repressor turns on only if there is tryptophan (a corepressor)

Repressible and Inducible Operons

• Repressible operons are usually on - repressor binding shuts down transcription
• The trp operon is a repressible operon
• Inducible operons are usually off - inducers will inactivate the repressor to turn on transcription
• The lac operon is an inducible operon containing genes that will code for enzyme used to hydrolyze and metabolize lactose
• The lac repressor is naturally active thus lac operons are switched off without inducers
• An inducer molecule, like Allolactose, is needed to turn the lac operon on

Inducible vs Repressible Enzymes

• Inducible enzymes function in catabolic pathways and are induced by a chemical signal
• Repressible enzymes function in anabolic pathways and are repressed by high levels of an end product
• Regulation of the trp and* lac* operons involves negative control
• This is because the operons are switched off through the active form of the repressor

Positive Gene Regulation

• Some operons are controlled positively using a stimulatory protein
• An example stimulatory protein is Cyclic AMP receptor protein (CRP), an activator of transcription
• Cyclic AMP (cAMP) activates CRP under scarce glucose conditions
• Activated CRP enhances RNA polymerase affinity and therefore accelerates transcription
• CRP detaches when glucose levels rise, transcription rate will return to normal
• CRP also regulates other operons which encode enzymes used in catabolic pathways
• The ability to catalyze compound like lactose allows cells to survive even if they are deprived of glucose
• Compounds present in cells will determine which genes are switched on

Eukaryotic Gene Regulation

• All organisms must regulate which genes are expressed
• Genes are tuned on/off to respond to internal and external environments of a cell
• Gene expression regulation is essential in cell specialization for multicellular organisms

Differential Gene Expression

• Differential gene expression is the expression of different genes of the same genome
• Differences in cell type are the result of differential gene expression
• Gene abnormalities can lead to disease like cancer
• Gene expression is often associated with transcription
• Stages of gene expression that can be regulated in eukaryotic cells includes chromatin modification, DNA unpacking, transcription, RNA processing, translation, degradation of mRNA, protein processing and degradation.

Chromatin Structure

• Heterochromatin is tightly packed DNA, comes in multiple varieties, functions range from gene expression silencing to restraining DNA
• Chromatin's structural organization helps regulate gene expression in many ways
• Genes inside packed heterochromatin are not usually expressed
• Both genes expression and chromatin structure are influenced by chemical modification to histone and DNA of chromatin
• Chromatin is made of repeating nucleosome units - these consist of 146 bp DNA wrapped around dimers of 4 histone proteins

Histone Modification and DNA Methylation

• Histone acetylation includes the attachment of acetyl groups to amino acids in a histone tail
• histone acetylation seems to open up structures of chromatin and therefore aids the start of transcription
• Adding methyl groups can condense chromatin, which reduce transcription
• Reduced transcription in some species is associated with DNA methylation - the addition of methyl groups
• DNA methylation can also cause long-term inactivation of gene during cellular differentiation
• Genomic methylation regulates expression of paternal / maternal alleles to genes at the start of life

Epigenetic Inheritance

• Chromatin modifications may be passed to future cell generations, even though it does not alter the DNA sequence
• Epigenetic inheritance is the inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence

Transcriptional Gene Regulation

• Multiple Control elements associate with most eukaryotic genes - these are non-coding DNA segments that serve as transcription factor binding sites
• Control elements and the transcription factors they bind are very important to proper gene expression regulation for varying cell types
• High transcription levels depend on control elements and specific transcription factors
• Proximal control elements are positioned close to gene promoters
• Distal control elements, or enhancers, can be distant from genes or inside introns
• Typically, enhancers are associated with individual genes

General Transcription Factors

• Optimal transcription through RNA polymerase requires the assistance of transcription factors
• General transcription factors are required for transcription of protein-coding gene
• TATA boxes bind a few general transcription factors inside promoters
• Proteins and other transcription factors, including RNA polymerase II, bind other transcription factors
• Only once the whole initiation complex assembles that RNA polymerase can move along the template of DNA
• It produces a complementary strand of RNA
• High levels of transcription depend on presence of specific transcription factors
• Protein-mediated bending enables bound activators to contact mediator proteins
• Mediator proteins works alongside general transcription factors situated at the promoter
• This aids the assembly and placement of the pre-initiation complex

Embryonic Development

• Cell differentiation is the process by which cells become specialized in structure and function
• Morphogenesis constitutes processes that give an organism shape
• Differential gene expression happens when genes are regulated differently throughout all cell types
• Programs of gene regulation are formed in eggs as cell divide

Cytoplasmic Determinants and Inductive Signals

• Cytoplasm contains a cell's RNA, proteins, and other substances, though distributed unevenly in the unfertilized egg
• Maternal substances inside the egg, cytoplasmic determinants, are influential in early development
• Cells include different cytoplasmic determinants when mitotically dividing which leads to different gene expression

Determining Factors of Cell Types

• Determination commits cells becoming a certain cell type
• Determination is precedes differentiation
• Production of tissue-specific proteins marks cell differentiation

Pattern Formation

• Pattern formation provides spatial organization of organs and tissues
• Pattern formation begins with establishment of major axes in animals
• Pattern formation is dictated by positional information - molecular cues that tells cells their location

Genetic Factors

• E.B. Lewis, C. Nusslein-Volhard, and E. Wieschaus got a Nobel prize for decoding pattern formation with Drosophila
• Lewis discovered homeotic genes which control pattern formation during embryonic, larval and adult stages
• Research into homeotic genes gave rise to evolutionary development al biology, also called, evo-devo

Cancer And Genetic Change

• The gene regulation systems that go wrong in cancer are some of the same systems used in embryonic development
• Mutations cause cancer, they change the genes and affecting cell-cycle control
• Cancer can be caused by mutations to genes which normally regulate cell growth and division
• Mutations inside cancer genes can come from spontaneous mutation or environmental reasons like radiation, and chemicals
• Viral mutations are also cancer causes

Oncogenes

• Oncogenes is cancer causing genes found in certain types of viruses
• Proto-oncogenes are corresponding normal cellular gene counterparts which account for regular cell growth and division
• Proto-oncogenes can be converted to oncogenes leading to abnormal cellular stimulation
• Proto-oncogene conversion can occur due to DNA movement inside the genome, Proto-oncogene amplification or its control elements and point mutations inside the proto-oncogene

Tumor-Suppressor Genes

• Tumor-suppressor genes naturally inhibit cell division
• Cancer onset occurs as a result of mutations that inhibit protein production of tumor-suppressor genes
• Tumor-suppressor proteins
  • Repair damaged DNA
  • control cell adhesion
  • act in cell-signaling pathways that inhibit the cell cycle

Proto-Oncogenes

• Common pathways to suppress through proto-oncogenes and p53
• Mutations in ras gene leads to increased cell division through increased Ras protein
• Ras protein is a G-protein that relays cell surface signals from a growth factor receptor
• Mutations inside p53 genes prevent suppression of the cell cycle
• DNA damage uses normal p53 proteins to prevent the passing of mutations.
• It activates miRNAs expression which halts cycle, turns on genes directly involved within DNA repair pathways
• P53 triggers cell 'suicide' genes when DNA is irreparable

Virus Role in Cancer

• Some animal and human tumor viruses also can cause cancer
• Viruses interfere with gene regulation if they are integrated in the DNA
• Viruses are powerful biological agents