10.2 Eukaryotic Transcriptional Regulation

Eukaryotic transcriptional regulation is a complex process involving multiple layers of control. From DNA elements like enhancers and silencers to transcription factors and epigenetic modifications, cells have numerous tools to fine-tune gene expression.

Understanding these mechanisms is crucial for grasping how cells respond to their environment and maintain proper function. This topic builds on earlier concepts of gene expression, highlighting the intricate ways eukaryotes control which genes are active and when.

Regulatory DNA Elements

Enhancers and Silencers

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• Enhancers boost gene transcription by binding activator proteins
  • Located far from the promoter, up to thousands of base pairs away
  • Can function in either direction and on multiple genes
  • Form DNA loops to interact with promoter regions
• Silencers repress gene transcription by binding repressor proteins
  • Similar to enhancers in location and function, but with opposite effects
  • Can act over long distances and through chromatin structures
• Both enhancers and silencers contain specific DNA sequences recognized by regulatory proteins
• Tissue-specific enhancers and silencers contribute to cell type-specific gene expression patterns

Promoter Elements

• TATA box serves as a binding site for RNA polymerase II and general transcription factors
  • Located about 25-35 base pairs upstream of the transcription start site
  • Consists of a consensus sequence TATAAA
  • Helps position RNA polymerase II correctly for transcription initiation
• Promoter-proximal elements regulate transcription from nearby genes
  • Located within ~200 base pairs upstream of the transcription start site
  • Include CAAT box, GC box, and other regulatory sequences
  • Bind specific transcription factors to modulate gene expression
• Promoter strength varies depending on the combination and arrangement of these elements
• Some genes lack a TATA box and rely on other promoter elements for transcription initiation

Transcription Factors and Machinery

Transcription Factor Structure and Function

• Transcription factors regulate gene expression by binding to specific DNA sequences
• Consist of two main domains:
  • DNA-binding domain recognizes and binds to specific DNA sequences
  • Activation domain interacts with other proteins to influence transcription
• Various types of DNA-binding domains (zinc finger, helix-turn-helix, leucine zipper)
• Can act as activators or repressors of gene expression
• Often work in combination to fine-tune gene expression levels

Basal Transcription Machinery

• RNA polymerase II synthesizes mRNA from DNA template in eukaryotes
  • Composed of 12 subunits
  • Requires additional proteins for accurate transcription initiation
• General transcription factors assist RNA polymerase II in transcription initiation
  • Include TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH
  • Form the preinitiation complex (PIC) at the promoter
• TFIID contains the TATA-binding protein (TBP) which recognizes the TATA box
• TFIIH possesses helicase activity to unwind DNA and kinase activity to phosphorylate RNA polymerase II
• Stepwise assembly of the PIC ensures accurate transcription initiation

Epigenetic Regulation

Chromatin Remodeling and Histone Modifications

• Chromatin remodeling alters DNA accessibility for transcription factors
  • ATP-dependent chromatin remodeling complexes (SWI/SNF, ISWI, CHD, INO80)
  • Slide, eject, or restructure nucleosomes to expose or conceal DNA sequences
• Histone modifications affect chromatin structure and gene expression
  • Include acetylation, methylation, phosphorylation, and ubiquitination
  • Histone acetyltransferases (HATs) add acetyl groups, promoting open chromatin
  • Histone deacetylases (HDACs) remove acetyl groups, promoting closed chromatin
  • Histone methylation can activate or repress transcription depending on the specific residue and degree of methylation
• Histone code hypothesis suggests combinations of modifications determine gene activity

DNA Methylation and Gene Silencing

• DNA methylation involves addition of methyl groups to cytosine bases
  • Occurs primarily at CpG dinucleotides in mammals
  • Catalyzed by DNA methyltransferases (DNMTs)
• Methylated DNA generally associated with transcriptional repression
  • Interferes with transcription factor binding
  • Recruits methyl-CpG-binding proteins that promote chromatin compaction
• DNA methylation patterns are heritable and contribute to cell type-specific gene expression
• Plays crucial roles in genomic imprinting and X chromosome inactivation
• Aberrant DNA methylation associated with various diseases, including cancer