Updated: 11/1/2017

Transcription Regulation

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Overview
  •  Function
    • can turn transcription on/off
    • can ↑ or ↓ rate of transcription
    • can act in cis or trans
      • cis = regulation near gene locus
        • DNA binding sequence
        • a mutated cis regulatory element can result in gene that is constitutively on or off
      • trans = regulation from gene locus
        • transcription factor protein
        • because it acts at a distance a good allelic copy can compensate for a mutated copy
  • Mechanisms of control 
    • modify RNAp binding stability
      • transcription factors
        • function
          • modify basal transcription levels
          • two types
            • general
              • must bind to DNA and RNAp to begin baseline transcription of most every gene
              • e.g. TFIID binds TATA box and RNAp II
            • specific
              • acts through enhancers and silencers
              • can regulate specific gene responses
        • structure
          • DNA binding domain
            • can be zinc fingers, helix-turn-helix, helix-loop-helix, or leucine zippers
          • regulatory element binding domain
            • e.g. binds hormone, ion, other transcription factors, etc.
    • modify RNAp accessibility to DNA
      • histone modifiers
        • histone acetylases (HATs) open DNA and ↑ transcription 
        • histone deacetylase (HDACs) close DNA and ↓ transcription
        • see Chromatin Structure topic
      • imprinting
        • methylation effectively shuts a gene off
          • often irreversible
        • some genes methylate a gene locus on paternal or maternal chromosome
          • allows only one allele to be active
          • e.g. Prader-Willi/Angelman syndrome
        • see Epigenetics topic
      • inactivation of a chromosome
        • condensation of # of X chromosomes - 1 to form Barr bodies
          • e.g. Turner's Syndrome (XO) the patient would have no Barr bodies as they only have 1 X chromosome
      • increase number of gene copies
        • more sites for RNAp to bind
        • common in oncogenes
  • Embryonic gene regulation
    • sonic hedgehog (SHH) gene
      • mutations causes holoprosencephaly (HPE)
        • failure of midline brain to separate into right and left
    • homeobox (HOX) genes
      • control proper timing of gene activation
    • paired box (PAX) genes
      • mutations cause Klein-Waardenburg syndrome
        • presentation
          • neural crest abnormalities
            • deafness
            • variation in pigmentation
              • forelock of white hair
              • patches of different colored skin
            • dystopia canthorum
              • broad nasal root
  • Examples of gene regulation
    • peroxisome proliferator-activated receptors (PPARs)
      • controls fat metabolism
        • turned on by endogenous ligands
          • fatty acids, prostaglandins
        • also turned on by exogenous ligands
          • fibrates, thiazolidinediones
      • bind PPRE region in DNA
      • clinical importance
        • fibrates given to hyperlipidemic patients to ↑ transcription of lipoprotein lipase
          • also used in treatment for Zellweger syndrome

 

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