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.