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• Regulation of Gene Expression

  • Ability of a cell to control or regulate what proteins it makes from its DNA
  • DNA-binding transcription factors are physically linked to their target promoter elements and either activate or repress gene transcription
  • DNA-binding transcription factors are composed of structurally and functionally distinct domains that directly or indirectly control gene transcription
  • Nucleosome-directed regulatory events typically increase or decrease the accessibility of the underlying DNA for transcription making it one mechanism of regulation of gene expression
• Gene expression is the process by which the information encoded in a gene is used to direct the assembly of a protein molecule
• The development of specialized organs, tissues, and cells, and their function in the intact organism depend on the differential expression of genes
• Controlling gene expression is critical to a cell to avoid wasting energy and raw materials in the synthesis of proteins it does not need
• Mechanisms of controlling gene expression involve modulation of gene transcription, gene amplification, gene rearrangement, posttranscriptional modification, RNA stabilization, translational control, protein modification, compartmentalization, stabilization, or degradation
• Mechanisms controlling gene expression are used to respond to developmental cues, growth factors, hormones, environmental agents, and therapeutic drugs
• Dysregulation of gene expression can lead to human disease
• Two Types of Gene Regulation: Positive regulation increases the expression of genetic information, negative regulation diminishes the expression of genetic information
• A double negative regulator has the effect of acting as a positive regulator
• Types of responses to a regulatory signal

  • Type A response
  • Type B response
  • Type C response
• Type A response


  Increased gene expression dependent on the continued presence of the inducing signal
• Type A response


  Amount of gene expression diminishes to its basal level when the inducing signal is removed, but repeatedly increases in response to the reappearance of the specific signal
• Type A response


  Commonly observed in prokaryotes in response to changes in nutrient concentration
• Type B response


  Exhibits an increased amount of gene expression that is transient even in the continued presence of the regulatory signal
• Type B response


  After the regulatory signal has terminated, a second transient response to a subsequent regulatory signal may be observed
• Type B response


  Commonly occurs during development of an organism when only the transient appearance of a specific gene product is required although the signal persists
• Type C response


  Exhibits an increased extent of gene expression that persists indefinitely even after termination of the signal
• Type C response


  The signal acts as a trigger in this pattern
• Type C response


  Once expression of the gene is initiated in the cell, it cannot be terminated even in the daughter cell
• Type C response


  It is an irreversible and inherited alteration, typically occurring during the development of differentiated function in a tissue or organ
• Unique features of prokaryotic gene expression

  • Genes involved in a metabolic pathway usually present in a linear array called an operon
  • Operons can be regulated by a single promoter or regulatory region
  • Cistron is a coding sequence or segment of DNA encoding a polypeptide
  • A single mRNA that encodes more than one separately translated protein is referred to as a polycistronic mRNA
• In prokaryotes, genes involved in a metabolic pathway are usually present in a linear array called an operon
• An operon can be regulated by a single promoter or regulatory region
• The cistron is a coding sequence or segment of DNA encoding a polypeptide
• A single mRNA that encodes more than one separately translated protein is referred to as a polycistronic mRNA
• An inducible gene is one whose expression increases in response to an inducer or activator, a specific positive regulatory signal
• The expression of some genes is constitutive, meaning that they are expressed at a reasonably constant rate and not known to be subject to regulation. These are often referred to as housekeeping genes
• As a result of mutation, some inducible gene products become constitutively expressed
• A mutation resulting in constitutive expression of what was formerly a regulated gene is called a constitutive mutation
• In 1961, Jacob and Monod described their operon model in a classic paper describing the regulation of lactose metabolism by the intestinal bacterium E. coli
• What was formerly a regulated gene is called a constitutive mutation
• Jacob and Monod described their operon model in a classic paper in 1961, describing the regulation of lactose metabolism by the intestinal bacterium E. coli
• Lac Operon


  • The gene encoding β-galactosidase (lacZ) is clustered with the genes encoding lactose permease (lacY) and thiogalactoside transacetylase (lacA)
• Lac Operon


  The genes encoding the enzymes, lac promoter, lac operator, and the lacI gene encoding the LacI repressor are physically linked and constitute the lac operon
• Lac Operon


  This genetic arrangement allows for coordinate expression of the three enzymes concerned with lactose metabolism
• Lac Operon


  The polycistronic mRNA molecule contains multiple independent translation start (AUG) and stop (UAA) codons for each of the three cistrons
• Each protein in the lac operon is translated separately and not processed from a single large precursor protein
• Protein coding and regulatory elements of the ~6kbp lac operon

  • lacZ encodes β-galactosidase
  • lacY encodes a permease
  • lacA encodes a thiogalactoside transacetylase
  • lacI encodes the lac operon repressor protein
• Components of lac operon

  • Transcription start site (TSS)
  • Operator - binding site for the LacI protein
  • Operator overlaps the lac promoter
  • cAMP response element (CRE) - binding site for cAMP activator protein (CAP), the positive regulator
• Mechanism of repression, derepression, and activation of the lac operon

  When no inducer is present, the constitutively synthesized lacI gene products form a repressor tetramer that binds to the operator, preventing transcription of the structural genes