Gene expression DNA RNA Protein DNA DNA Degradation RNA Degradation Protein Replication Transcription Translation Initiation Elongation Processing Export Initiation Elongation Processing Targeting
Chapter 7: Gene control Control of gene expression is critical in mediating cellular changes: Executing developmental programs Controlling cell cycle Responsiveness to regulators There are many examples of evolutionary variation in promoters and transcriptional regulators
Since all cells in an organism have the same DNA, how do the cells become different? (1) Some genes are expressed only in specific tissues (e.g., hemoglobin)
Since all cells in an organism have the same DNA, how do the cells become different? (2) Genes expressed in all cells are termed housekeeping genes: cytoskeleton building blocks metabolism histones, polymerases
Since all cells in an organism have the same DNA, how do the cells become different? (3) Even housekeeping genes are expressed at different levels -metabolic profiles of red and white muscle
Since all cells in an organism have the same DNA, how do the cells become different? (4) Post-transcriptional processes (Fig 7-5) also critical in regulating function: -mrna processing -mrna transport and localization -mrna degradation -translation -post-translational modification -3-dimensional organization -compartmentation -protein degradation
Fig 7-5. Gene expression is controlled at many levels
Cells can change expression in response to external signals Many cells use hormonal signals to trigger changes in gene expression: e.g., glucocorticoids induce changes in metabolic enzyme expression in liver
Cells can change expression in response to external signals Different cells respond differently to the same hormones: e.g., glucocorticoids in liver: induction of genes that enhance conversion of amino acids to glucose. -in adipocytes, glucocorticoids repress the same gene
Transcriptional control Genes are regulated by promoters (regions upstream of coding region) Genes can also be regulated at sites that are distant from promoters (even in introns)
Gene regulatory proteins Regulatory regions of DNA have short sequences (elements) that bind specific gene regulatory proteins e.g., Sp1 binds GGGCGG CCCGCC These proteins recognize subtle differences in the structure of the outside of the major groove of the DNA double helix
Gene regulatory proteins Each protein differs in how it binds DNA and how it interacts with other proteins Several common DNA binding motifs including:
-helix-turn-helix motif (Fig 7-14), include homeodomain proteins
-zinc finger proteins (Figs 7-17-19)
-leucine zippers (Fig. 7-21)
-helix-loop-helix (HLH) (Fig 7-25)
Gene regulatory proteins DNA binding ability of gene regulatory proteins can be influenced by: -localization -dimerization (homodimers vs heterodimers)
Tryptophan repressor is a simple model of ligand-dependent gene regulation (Fig-7-34, 7-35) Repressor protein can bind DNA and trp If trp absent, repressor cannot bind DNA (unrepressed) When trp available, repressor binds and prevents RNA Pol from binding gene
Eukaryotic gene expression What regulates transcription (Fig 7-41) Promoter: binding site for RNA Pol II and general transcription factors Other regulatory sequences can be far away (even 50,000 bp) Activators (or enhancers) bind to specific DNA sequences (modify local DNA structure)
Eukaryotic gene expression
Gene activators Activators can work synergistically (Fig 7-47) Order of binding of activators and combination of activators influences transcription (Fig 7-48)
Gene repressors Repressors can work many different ways (Fig 7-49) -competition with activators for sites -masking activation site on activator -disruption of general transcription factors -affecting chromatin remodelling
Co-activators and co-repressors These proteins do not bind DNA but bind DNAbinding proteins (Fig 7-50)
Myogenesis: an example of programmed transcriptional regulation (Fig 7-72) Precursor cells are myoblasts Hormonal conditions cause differentiation: turning on suites of muscle-specific genes in the appropriate order Hormones induce expression of myogenic factors (transcription factors)
Control of gene expression 1. Localization of transcription factors Hormone kinase kinase X
Control of gene expression 2. Dimerization Hormone kinase kinase
Control of gene expression 3. Affinity for DNA (phosphorylation dependent) Hormone kinase kinase
Control of gene expression 4. Affinity for DNA (ligand dependent) Hormone
Control of gene expression 5. Affinity for DNA (ligand dependent) Hormone