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.