Transcriptional Control of Gene Expression

Transcriptional Control of Gene Expression

• Inactive genes are packaged into condensed chromatin, inhibiting RNA polymerase and general transcription factors needed for transcription initiation.
• Transcriptional control primarily focuses on regulating transcription initiation and elongation, determining gene expression levels and the quantity of mRNA and protein production.
• Activator proteins bind to control elements (both near and distant to the initiation site) to promote chromatin decondensation, enhancing transcription.
• Repressor proteins bind to different control elements, leading to chromatin condensation and inhibiting transcription.
• All cells within an organism share the same genome, but not all genes are expressed in every cell.
• Gene expression levels vary both among cell types and within the same cell at different times.
• Prokaryotes control gene expression primarily at the transcription level due to the absence of mRNA processing.
• Eukaryotes utilize multi-level control, including transcription, RNA processing, translation, and post-translational modification.
• Transcription control is the most common regulatory mechanism in eukaryotes.
• RNA polymerase is responsible for RNA synthesis during transcription, initiating transcription at DNA sequences corresponding to the 5' cap of mRNA.
• Three types of eukaryotic RNA polymerase exist, each specializing in transcribing genes encoding different RNA classes.
  • RNA polymerase I located in the nucleolus, transcribes pre-rRNA, which is processed into 28S, 5.8S, and 18S rRNA.
  • RNA polymerase II transcribes all protein-coding genes (mRNA) and four of the five small nuclear RNAs involved in RNA splicing (U1, U2, U4, U5) as well as microRNAs (miRNAs).
  • RNA polymerase III transcribes genes encoding tRNA, 5S rRNA, and a variety of small stable RNAs including U6 (involved in RNA splicing), and the RNA component of the signal recognition particle (SRP).
• The SRP is involved in directing newly synthesized proteins to the endoplasmic reticulum.
• Prokaryotes have only one type of RNA polymerase, while eukaryotes have three.
• RNA polymerase core subunit structures exhibit extensive similarity across diverse organisms, indicating their early evolutionary origin and conservation.
• Transcriptional control regions include promoters, promoter-proximal elements, and distal enhancers.
• Promoters are DNA sequences specifying RNA polymerase binding sites, initiating transcription, and influencing the transcription rate.
  • TATA box: located -25 to -35bp upstream of the start site, the most common type.
  • Initiator: alternative promoter element, with less defined boundaries.
  • CpG island: found in many constitutive genes, enabling transcription at low rates.
• Promoter-proximal elements play a role in regulating eukaryotic genes.
  • Located between 100-200bp upstream of the transcription start site.
  • Sometimes, these elements exhibit cell-type specificity.
• Distant enhancers stimulate transcription by RNA polymerase II in eukaryotes, influencing chromatin structure.
  • Located far from the transcription start site.
• Acetylation and deacetylation of lysine residues in histone tails influence how tightly DNA is bound by histones, affecting chromatin condensation levels.
• Heterochromatin is densely packed, transcriptionally inactive chromatin, while euchromatin is less condensed, transcriptionally active chromatin.
• Transcription activators and repressors primarily influence the assembly of pre-initiation complexes by modulating chromatin structure (indirect effect) or interacting with RNA polymerase II and general transcription factors (direct effect).
  • Multiple DNA-bound activators can cooperate through a single mediator complex, integrating signals from different activators at a single promoter.
• Signals, receptors, and transcription factor activity play crucial roles in regulating transcription.
  • Chemical signals commonly alter transcriptional rates, binding to cellular receptors.
  • Receptors can be either cell surface receptors (for hydrophilic signal molecules) or nuclear receptors (for hydrophobic signals).
• Small lipid-soluble hormones can readily traverse plasma and nuclear membranes, directly interacting with transcription factors they control, often acting as transcription activators.
• The nuclear receptor superfamily of transcription factors share a common domain structure.
  • Variable-length N-terminal region with an activation domain.
  • DNA-binding domain with repeated Zn2+ finger motifs.
  • C-terminal hormone-binding domain containing a ligand-dependent activation subdomain.
• Homodimeric nuclear receptors are located in the cytosol in the absence of ligands.
  • Ligand binding causes the complex to translocate to the nucleus and activate transcription of target genes.
  • Example: Glucocorticoid receptor.
• Heterodimeric nuclear receptors reside in the nucleus.
  • Examples: Estrogen receptor, Vitamin D receptor, Retinoic acid receptor.
  • In the absence of ligands, they bind to their cognate DNA, inducing histone deacetylation and suppressing transcription.
  • Ligand binding directs histone hyperacetylation with HAT (unwinding DNA) and stimulates the pre-initiation complex, enabling transcription.