Epigenetic control of Gene Regulation Epigenetic vs genetic inheritance Genetic inheritance due to differences in DNA sequence Epigenetic inheritance.

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  • Epigenetic control of Gene RegulationEpigenetic vs genetic inheritanceGenetic inheritance due to differences in DNA sequenceEpigenetic inheritance not due to differences in DNA sequece

  • Epigenetic control of Gene RegulationDNA methylation is key to epigenetic control of gene regulationMethylated DNA typically associated with inactive chromatin/GenesUnmethylated DNA associated with transcribed DNA/GenesDNA methylation may play a role as a defense mechanism againts transposable elements but certainly plays a regulatory role in gene regulationSome but not all genes contain very high densities of CpG methylation sites specifically in promoter regions

  • Inheritance of Methylation statusMethylation occurs at CpG motifs in mammalsCytosine methyltransferases have preference for hemi-methylated DNA and methylate methylated opposite strand- results in inheritance of methylation status.

  • Mechanism of transcriptional inactivation by DNA methylationH3 K9 key regulator in gene silencing

  • Histone modification Histone acetylation - generally associated with promoter activation (histone deacetyleses (HDACs) inhibit transcription Neutralizes basic charges on lysines and arginine residues - relaxes nucleosome Allows direct binding of activating proteins to promoter bound histones Histone methylation Arginine methylation associated with promoter activation Lysine methylation associated with promoter inactivation

  • Inheritance of Suppressed PromotersMaintains suppressed gene expression as cells divideInvolved in X inactivationDosage compensationImprinting occurs in early embryo and is random with respect to Xp or Xm inactivationFemale mammals are therefore mosaicsCalico cat

  • Gene Regulation Through Somatic RecombinationImmune Function (Ig and TCR) Generates complexity for recognition of diverse antigens

    B-cellsHeavy Chain (H-chain locus)Light Chain (lambda and Kappa loci)T-cellsAlpha and Beta lociGamma and Delta loci (expressed on small fraction of T cells

  • Structure of Ig Heavy Chain Locus- Differential recombination of individual V, D and J loci generate initial diversity in Heavy chain gene for individual cell. - Similar recombination occurs in either kappa or lambda light chain loci- Resulting heterodimers of H and L provide wide array of diverse structural motifs for diverse antigen recognition

  • Step 1 - Variable region Recombination- Recombination signaling sequences flank each V, D, and J segment which specify recombination VDJ as well as VJ recombination can occur Results in unique variable region which splices to M constant region (produces membrane IgM)(Immature nave B cell) Mature nave B cell expresses heavy chains with M as well as D constant region Both of these are membrane bound Antigen recognition leads to production of secreted form of IgD which provide initial immune response

  • Step 2 - Somatic MutationEngagement of IgM with antigen causesConversion to secreted form of IgMProliferation of immature B cellSomatic mutation of variable regionsCells with higher affinity receptors stimulated preferentially by antigen to further proliferate and undergo class switching (step 3)

  • Step 3 - Class Switching

  • Step 3 - Class Switching- Further recombination to G, A, or E constant regions generates secretory antibodies with specificity to same antigen but with different immune functions- IgG - binds complement and binds Fc receptors on macrophages and neutrophils- IgA - constant region recognized by Fc receptor on secretory epithelial cells for secretionto salive, tears, milk, respiratory and intestinal secretions.- IgE - Bind Fc receptors on mast cells and basophils causing secretion of cytokines and histamine.