Transcription Factors & Gene Regulation

Transcription Factors

  • Regulatory proteins that control gene expression by acting in trans.
  • Two classes:
    • General transcription factors: drive RNA polymerase function.
    • Site-specific transcription factors: recognize specific DNA elements; can activate or repress genes.
  • Site-specific factors recruit co-regulators to drive transcription.

Core Promoter and General Transcription Factors

  • General transcription factors bind to the core promoter region, initiated by the TATA binding protein (TBP) recognizing the TATA box.
  • Recruitment occurs stepwise, forming the pre-initiation complex.
  • TFII (transcription factor for class II genes) factors assemble, with TFIIH unwinding DNA and phosphorylating polymerase II to activate transcription.
  • The pre-initiation complex is a megadalton complex with a detailed structure elucidated by X-ray crystallography and cryo-electron microscopy.

Site-Specific Transcription Factors

  • Bind to promoter elements and can be modulated by environmental stimuli.
  • Dynamic process with factors binding and unbinding to modulate transcription.
  • Typical transcription factor protein structure:
    • DNA binding domain: recognizes specific DNA sequences.
    • Dimerization domain: allows for homo- or heterodimer formation.
    • Regulatory region: interacts with external signals (e.g., hormones).
    • Transactivation domain: interacts with co-regulators.

DNA Binding Domains

  • Classified based on structures like zinc finger, recognizing specific DNA sequences.
  • Estrogen receptor binds to the estrogen response element (ERE), a symmetrical sequence with a three-nucleotide spacer.

Activation and Repression

  • Activators recruit general transcription factors to drive transcription.
  • Enhancer zones enhance transcription rates by speeding up polymerase recruitment.
  • Repressors reduce or prevent transcription by:
    • Preventing polymerase binding.
    • Disrupting enhancer zones.
    • Steric hindrance of activator binding.

Co-regulators

  • Recruited by site-specific transcription factors; do not bind DNA themselves.
  • Co-activators enhance transcription by:
    • Interacting with the pre-initiation complex (e.g., via the Mediator complex).
    • Modifying chromatin structure (e.g., histone acetyltransferases opening chromatin).
  • Co-repressors silence genes by:
    • Destabilizing activation complexes.
    • Modifying chromatin structure (e.g., histone deacetylases closing chromatin).

Mediator Complex

  • A multi-subunit protein complex with head, middle, tail, and CDK kinase regions.
  • Enhances activated transcription by mediating signals from transcription factors.

Co-repression

  • An active process involving specific proteins that turn off transcription.
  • Recruit proteins that destabilize activation complexes or change chromatin structure.

Integration of Transcription and Epigenetics

  • Chromatin structure and transcription are interconnected; chromatin must be open for transcription to occur, and transcription must stop for chromatin to close.