Gene Expression and Epigenetics

Gene Expression Patterns

• Gene expression is primarily regulated during interphase
• Most transcription and synthesis processes stop during mitosis
• Some mechanisms maintain stable gene expression, even without changing DNA sequences

Epigenetic Regulation

• Epigenetics modifies gene expression without changing DNA
• Essential for cellular differentiation (e.g., liver cells remain liver cells)
• Stem cells differentiate into diverse cell types.

Four Mechanisms of Epigenetic Regulation

• Positive Feedback Loops
  • A protein activates its own transcription
  • Maintains its expression even after the initial signal ends
  • Ensures stable gene expression until a new signal comes
• Covalent Histone Modifications
  • Chemical modifications of histones (e.g., acetylation, methylation) change chromatin accessibility
  • Ensures stable gene expression patterns across cell generations

DNA Methylation

• Methyl groups added to CpG sequences silence genes
• Maintenance methyltransferase preserves methylation patterns during DNA replication
• Newly synthesized DNA strands are initially unmethylated and then methylated to match the template strand

Protein Aggregates

• Proteins can fold into different states, some of which are pathological (e.g., prions)
• Pathological protein folding can be a stable epigenetic change, affecting conditions like Alzheimer's and Parkinson's

Epigenetic Regulation and Cellular Differentiation

• Epigenetics allows cells to retain specialized functions across divisions.
• Stable epigenetic changes facilitate tissue and organ function in multicellular organisms.

Cellular Transport and Topological Compartments

• Cytoplasmic to Nuclear Transport
  • Molecules enter and exit the nucleus
  • Transport occurs between topologically similar areas
• Transmembrane Transport
  • Movement across membranes between cytosol and organelles (e.g. ER, mitochondria)
• Vesicular Transport
  • Transport between organelles
  • Involves vesicles that carry cargo while maintaining the topology of the membrane

Gated Transport: Nuclear-Cytosol Exchange

• Nucleus and cytosol are topologically similar due to the continuity of the nuclear envelope and ER membrane.
• Nuclear Pore Complex (NPC)
  • Acts as a selective gateway between the nucleus and cytosol.
  • Small molecules can diffuse freely through the NPC while larger ones require active transport.
  • Specific signal sequences are needed for import and export, recognized by nuclear transport receptors

Transmembrane Transport: Crossing Membranes

• Proteins cross the lipid bilayer using translocators.
• Proteins are often unfolded to pass through translocators and then refolded.

Vesicular Transport: Between Topologically Equivalent Compartments

• Vesicular transport is the movement of proteins between compartments that share the same topological orientation.
• Protein orientation is preserved during transport.
• Vesicles are created to move cargo.

Shared Features of Transport Mechanisms

• Involve protein recognition and sorting for delivery to correct destinations
• Signal sequences (e.g., NLS, NES) specify location

Nuclear Transport and Ran-GTP Gradient

• Crucial for moving proteins and other macromolecules between the nucleus and cytosol.
• Ran-GTP Gradient creates directional transport.
  • High Ran-GTP concentration is in the nucleus
  • High Ran-GDP concentration is in the cytosol
• Ensures that proteins move in one direction
• Mechanisms of Nuclear Transport:
  • Import
    • Cargo with NLS binds to import receptors
    • Complex moves through NPCs
    • Ran-GTP causes cargo release.
    • Release receptor & Ran-GTP returns to the cytosol
  • Export
    • Cargo with NES binds export receptors, & Ran-GTP.
    • Complex moves into cytosol
    • Ran-GTP hydrolysis releases cargo.
    • Releasing export receptor to return.

Integration of Concepts

• Connecting signal sequences (NLS, NES) & Ran Gradient;
• Coordinate between components (NPC, Ran) for efficient, unidirectional transport
• Using energy from ATP hydrolysis

Mitochondrial Protein Import and Transport Mechanisms

• Mitochondria evolved from endosymbiotic organisms
• Many mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria.
• Proteins utilize import signals (amphipathic alpha-helices) when moving through the mitochondrial membranes, altering orientation to enter different compartments (e.g., outer membrane, intermembrane space matrix)
• Import Machinery (Tom and Tim complexes) help in bringing the proteins into mitochondria
• Chaperone Proteins assists during import and ensure proteins fold correctly in the mitochondria

Vesicular Transport Models and Membrane Trafficking

• Vesicles move proteins and other materials between compartments
• Compartments sometimes change over time (e.g., Golgi cisternae maturation)
• Both models (vesicles as independent "elevators" & compartmental change) work together in the cell
• Retrograde transport plays a role in Golgi and ER functions

Exocytosis and Membrane Protein Transport

• Vesicles fuse with the plasma membrane to release materials
• Rabs and SNAREs mediate vesicle docking and fusion.
• Regulated secretion involves specific signals (e.g., hormonal), while constitutive secretion happens automatically.

Coated Vesicles and Coat Proteins

• Proteins help form vesicles
• COPI, COPII, and clathrin are involved in various transport processes.
• Each has a particular function (e.g. COPI is involved in retrograde transport from the Golgi
• COPII from ER to Golgi)
• Ensures materials in vesicles are transported to the right location

Dynamin in Vesicle Budding

• Dynamin is a GTP-binding protein involved in vesicle severing from the parent membrane.

Lysosomal Targeting and Retrograde Transport

• Cargo destined for degradation (e.g., proteins) is transported to lysosomes using signals
• Mannose-6-phosphate (M6P) and recognition are important components
• Transport towards lysosomes via anterograde direction.
• Receptors are part of the retrograde transport pathway (back to Golgi) to recycle.

ATP and GTP in Vesicular Transport

• GTP plays a role in vesicle assembly, docking, and budding, and ATP is used in processes involving membrane fusion
• Energy required in vesicle trafficking and proteins.

Additional Key Points

• Targeting signals: Critical for correct delivery of cargo
• Signal sequences: guide proteins to their destinations
• Different types of transport: (Gated, transmembrane, and vesicular) each having particular function & mechanism
• Membrane topology: important to ensure correct orientations of proteins and materials inside membranes
• Energy sources: ATP & GTP gradients drive many of these processes

Explore the intricate world of gene expression regulation and epigenetic modifications. This quiz covers the mechanisms of gene expression during interphase, the role of epigenetics in cellular differentiation, and key regulatory processes such as histone modifications and DNA methylation. Test your understanding of how genes can be expressed without altering the DNA sequence.