SCH2226 Human Molecular Genetics - Lecture 10 Flashcards

Operons in Eukaryotes

  • Occurrence: Contrary to historical belief, eukaryotes like the nematode C. elegans possess operons. Approximately 15%15\% of C. elegans genes are in operons ranging from 2–82\text{--}8 genes.

  • Structure: Controlled from a single promoter producing polycistronic mRNA.

  • Processing: Resolved into monocistronic mRNAs through trans-splicing (using SL RNA) and polyadenylation/cleavage.

  • Function: Unlike prokaryotes, eukaryotic operon genes often have unrelated functions.

Levels of Control and Transcription Initiation

  • Regulatory Complexity: Eukaryotes have more complex regulation than prokaryotes due to condensed chromatin and larger genomes.

  • Levels of Control: Transcription, mRNA processing/transport, translation, mRNA degradation, protein processing, and protein degradation.

  • Transcription Initiation: The primary control level involving activators binding to promoter elements (proximal) and enhancer elements (distal) to recruit transcription machinery.

Chromatin Remodeling

  • Mechanism: Modification of chromatin structure to make promoters accessible.

  • ATP-Dependent Complexes: Use energy to alter nucleosome positions.

  • Acetylation:

    • Histone Acetyl Transferases (HATs): Add acetyl groups to lysines in core histones, changing 30–nm30\text{--}nm chromatin to 10–nm10\text{--}nm fiber to increase accessibility.

    • Histone Deacetylases (HDACs): Remove acetyl groups to reform 30–nm30\text{--}nm chromatin, making the process reversible.

Combinatorial Regulation and Hormones

  • Combinatorial Control: Different combinations of specific activator and repressor proteins control the transcription of specific genes.

  • Steroid Hormones: Effector molecules that bind cytoplasmic receptors (e.g., steroid hormone receptor, SHR). The complex binds directly to DNA to regulate gene expression (e.g., testosterone for male characteristics or progesterone for uterine lining maintenance).

Post-Transcriptional Regulation

  • Alternative Processing: Includes alternative polyadenylation and differential (alternative) splicing.

  • Outcome: Allows the production of structurally and functionally different proteins from the same gene (e.g., the human calcitonin gene, CALC).

RNA Interference (RNAi)

  • Definition: A mechanism that inhibits gene expression by hindering transcription or translation. Terms include co-suppression (plants), quelling (fungi), and RNAi (animals).

  • Core Players:

    • Dicer: An ATP-dependent RNase III-like enzyme that cleaves dsRNA into siRNAs (20–25 bp20\text{--}25\text{ bp}).

    • siRNA: Small interfering RNA fragments (21–25 nt21\text{--}25\text{ nt}) with 5′-phosphate5'\text{-phosphate} and 3′-hydroxyl3'\text{-hydroxyl} termini.

    • RISC: RNA-Induced Silencing Complex; incorporates siRNA and uses argonaute proteins (endonucleases) to cleave target mRNA.

  • Biological Importance: Defense against viruses and transposons; regulates 30%30\% of the human genome.

  • Therapeutic Potential: Explored for oncology (targeting oncogenes), hematology, and infectious diseases (e.g., Hepatitis C research by Anton McCaffrey and Mark Kay; Huntington's Disease research by Beverly Davidson).

Antisense Oligonucleotides

  • Structure: Synthetic polymers (15–2015\text{--}20 nucleotides long) with a sequence (3′→5′3' \rightarrow 5') complementary to the target mRNA sense sequence.

  • Function: Bind to target mRNA to block translation or inactivate the gene product, effectively turning the gene "off."