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Updated: Nov 1 2017

Transcription Regulation

  • 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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