--- module: 091-03 language: en chapter: 91 title: "DNA Replication, Repair, Gene Expression, and Epigenetic Control" module_title: "Translation, protein targeting, chromatin, epigenetic memory, and regulated expression" source_sha256: f4dfd75df2f98ac7d467cbbdb1662ec88233708ce622d926cd91a536d7e04f6c --- # Translation, chromatin, and epigenetic control ## Genetic code and transfer RNA ### Nonoverlapping triplets: 61 sense, 3 stop ### Degenerate, but each codon one amino acid ### Reading frame set at initiation #### Non-triplet indels shift downstream codons ### Synthetases charge transfer RNAs using ATP #### Editing sites remove wrong amino acids #### Ribosome cannot check amino acid identity ### Wobble at the third codon position ### No simple universal codon speed code ## Ribosome and translation cycle ### Ribosomal RNA forms peptide bonds: a ribozyme ### Aminoacyl, peptidyl, and exit sites ### Cap-dependent scanning to a favourable AUG #### Upstream ORFs, structure, factor phosphorylation ### GTP factors deliver and translocate ### Polysomes, speed shapes folding ### Release factors at stop codons #### Premature stop: decay or truncation #### Readthrough is variable ## Energy and growth control ### ATP to AMP per activation, GTP in elongation ### Stress phosphorylates initiation factors #### Selected stress transcripts continue ### mTORC1 drives synthesis, suppresses autophagy ### AMP-activated kinase restrains at low energy ### Excess drives cancer, suppression causes wasting ## Protein targeting and maturation ### Signal peptide directs proteins to the ER #### Anchors and stop-transfer set topology #### Luminal domains become extracellular ### Nuclear signals, importins, Ran ### Mitochondria: amphipathic helix, translocases ### Peroxisomes can import folded proteins ### Mannose-6-phosphate tags lysosomal enzymes ### Folding, modification, assembly give function #### Mislocalisation causes disease despite activity ## Chromatin structure ### Octamer of H2A, H2B, H3, H4 pairs #### About 147 base pairs per nucleosome #### Linker DNA and H1 for higher order ### Nucleosome positions are dynamic ### Acetylation weakens charge, opens chromatin ### Methylation meaning depends on residue ### ATP remodellers slide, eject, replace ### Histone variants specialise regions ### Pioneer factors open closed chromatin ## DNA methylation and epigenetic memory ### Methylation mainly at CpG cytosines #### CpG-island methylation: stable repression ### Maintenance copies hemimethylated DNA ### De novo enzymes set new patterns ### TET enzymes support demethylation ### Heritable through mitosis, not immutable #### Germline and early embryo reprogramming #### Some imprints escape erasure ## Imprinting and X inactivation ### Expression by parent of origin #### Same region, different syndromes #### Gene specific, not genome-wide ### XIST coats the future inactive X #### Repressive chromatin forms Barr body ### Random inactivation gives mosaicism #### Escape genes and skewing modify disease ## Genome architecture and cell identity ### Cohesin extrudes loops ### Boundary proteins define TADs #### Lost boundary misactivates genes ### Lamina-associated regions repressed ### Factor networks: feedback, cross-repression ### Induced pluripotency resets somatic state #### Residual epigenetic memory may remain ## Interpreting regulated expression ### Blood methylation may reflect cell mix ### Human transgenerational inheritance hard to prove ### Expression measured at many layers #### Discordance between layers is common ### Chain of conditional permissions #### Function matters more than exon position