Control of gene expression Transcriptional Post-transcriptional Epigenetics and long range control

Control of gene expression Transcriptional –Tissue specific transcription factors –Binding of hormones, growth factors etc. to response elements –Use of alternative promoters in a single gene

Control of gene expression Post-transcriptional –Alternative splicing –Alternative polyadenylation –Tissue specific RNA editing –Translational control mechanisms

Control of gene expression Epigenetics and chromatin structure –Allelic exclusion (rearrangements, imprinting, X inactivation) –Long range control by chromatin structure (position effects Pax6 in aniridia) –Cell position-dependent, short range signaling

Control of gene expression rRNA synthesis –Arrows indicate cleavage sites

Control of gene expression Initiation of transcription (RNA pol I) Initiation of transcription (RNA pol II)

Control of gene expression tRNA and 5s RNA promoter elements Initiation of transcription (RNA pol III)

Control of gene expression Conserved locations of promoter elements in eukaryotes

Control of gene expression Insulin gene promoter organization –NREnegative regulatory element –CREcAMP response element

Control of gene expression HS-40 alpha-globin regulatory site –Tissue specific regulation (many sites)

Control of gene expression Structural domains in transcription factors –HTH –HLH –Zn Finger –Alpha-helix

Control of gene expression Binding of conserved motifs to double helix

Control of gene expression Steroid receptors and response elements –GR –ER –PR –RAR –TR –VDR

Control of gene expression Transcription regulation by glucocorticoids

Control of gene expression Target gene expression via signal transduction –Protein kinase: hormonal signaling through cAMP-pt kinase A pathway –Cytoplasmic transcription factor NF kappa B and translocation to the nucleus

Control of gene expression Major Classes of Cell Surface Receptor –G protein coupled –Serine-Threonine kinase –Tyrosine kinase –Tyrosine kinase associated JAK (janus protein kinase) activity in JAK-STAT signaling –Ion channel-linked

Control of gene expression Secondary Messengers in Cell Signaling –Cyclic AMP (cAMP) –Cyclic GMP (cGMP) –Phospholipids/Ca

Control of gene expression The IRE binding protein and iron-response elements (IREs)

Control of gene expression Genes with multiple promoters –Dystrophin has eight promoters

Control of gene expression Differential RNA splicing –Wt1 Wilm’s tumor (four splice forms) –Calcitonin gene (tissue specific products)

Control of gene expression Tissue specific RNA editing –Apolipoprotein B gene (rare)

Control of gene expression Methylation and gene expression –Largely confined to CpG dinucleotides –CpG islands –Methylation patterns change during development –Sex-specific regulation

Control of gene expression Methylation –CpG islands

Control of gene expression Methylation –Changes in methylation throughout development

Control of gene expression Methylation –Sex-specific regulation of the Dnmt1 methyl transferase gene –1sosomatic –1spspermatocytes –1oooocytes

Control of gene expression Transcriptional repression by histone deacetylation –Mediated by methylation –Methylated CpG’s bound by MeCP2 repressor

Control of gene expression Gene clusters –Coordinated switching –Locus control region –Globin genes

Control of gene expression Imprinting –DNA methylation key component –Selective expression of genes –Nonequivalence of maternal and paternal genomes

Control of gene expression Monoallelic expression from biallelic genes –Allelic exclusion according to parent of origin Genomic imprinting –Allelic exclusion independent of parent of origin X-chromosome inactivation Programmed DNA rearrangement Unknown mechanism

Control of gene expression Programmed rearrangement –Ig and TCR loci in B and T lymphocytes

Control of gene expression Programmed rearrangement –Ig heavy chain locus on 14q32 86 variable (V) sequences 30 diversity (D) sequences 9 joining (J) segments 11 constant (C) sequences

Control of gene expression Programmed rearrangement –Light chain synthesis Somatic recombination V to J RNA splicing VJ to C –Heavy chain synthesis Two sequential somatic recombination events yield DJ and VDJ RNA splicing VDJ to C Somatic recombination VDJ to different C (switching)

Control of gene expression Inversion or deletion based splicing –Ig kappa light chain V-J splicing