Regulation of Gene Expression

Regulation of Gene Expression

Gene expression is regulated at multiple levels to allow cells to respond to environmental signals, differentiate, and specialize. Regulation is far more complex in eukaryotes than prokaryotes.

Prokaryotic Gene Regulation — Operons

Prokaryotes use operons — clusters of functionally related genes under one promoter, regulated together.

  • Lac Operon (Inducible; Jacob-Monod): Genes for lactose metabolism (lacZ, lacY, lacA). When glucose absent and lactose present: Allolactose (inducer) binds repressor → repressor dissociates from operator → transcription occurs. Also requires positive control: Absence of glucose → ↑cAMP → CAP (CRP) + cAMP binds to CAP site → enhances transcription. Catabolite repression: Glucose inhibits even if lactose present (preferred carbon source).
  • Trp Operon (Repressible; attenuation): Genes for tryptophan biosynthesis. Tryptophan (corepressor) binds Apo-repressor → Repressor complex binds operator → represses transcription. Also: Attenuation — when Trp abundant, ribosome does not stall at leader sequence → forms termination hairpin → premature transcription termination.

Eukaryotic Gene Regulation — Multiple Levels

  • Chromatin Remodeling: Nucleosome repositioning by SWI/SNF complexes; acetylation of histones (by HATs) → relaxed chromatin → active transcription; deacetylation (HDACs) → repression.
  • DNA Methylation: CpG islands methylated → gene silencing; often at promoters of tumor suppressor genes in cancer (epigenetic silencing). Maintained by DNMT enzymes.
  • Transcription Factor Binding: Sequence-specific transcriptional activators (e.g., SP1, AP-1, NFκB) and repressors bind enhancers or silencers → regulate RNA Pol II through Mediator complex. Enhancers can be >100kb away from promoter (DNA loops).
  • Post-transcriptional: Alternative splicing; mRNA stability (3'UTR elements, ARE sequences); polyadenylation site choice; miRNA (RISC complex).
  • Translational regulation: 5'UTR secondary structures; upstream ORFs; IRES; cap-independent translation during stress; specific RNA-binding proteins.
  • Post-translational: Ubiquitin-proteasome degradation; phosphorylation; localization.

Epigenetics

Heritable changes in gene expression WITHOUT changes in DNA sequence. Mechanisms:

  • DNA methylation (5-methylcytosine at CpG)
  • Histone modifications (acetylation, methylation, phosphorylation, ubiquitination)
  • Non-coding RNAs (miRNA, lncRNA, siRNA)
  • Chromatin remodeling

Epigenetic changes regulate: development, X-inactivation, genomic imprinting (IGF2/H19 locus; Angelman vs Prader-Willi syndromes), cancer (tumor suppressor silencing by methylation).

Transcription Factor Domains

  • DNA-binding domains: Helix-turn-helix (HTH), Zinc finger (Cys₂His₂), Leucine zipper, Helix-loop-helix (HLH)
  • Activation domains: Acidic activation domain, glutamine-rich, proline-rich
  • Nuclear receptors (steroid, thyroid hormones): Contain both domains; ligand binding activates; bind HRE as dimers