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Biol115 The Thread of Life" Lecture 11" Regulation of gene expression II: " Eukaryotic Transcription and cellular differentiation" The body is a community made up of its innumerable cells or inhabitants" ~Thomas A. Edison" Principles of Biology" • Chapter ‘Eukaryotic gene regulation’." Biol115_2014_Lecture 11" 2" Objectives" • Describe the variety of mechanisms for gene regulation in eukaryotic cells." • Describe the role of chromatin (chromosome folding) in gene regulation." • Explain how transcription factors offer multiple opportunities for gene regulation." • Explain how gene expression is co-ordinately controlled in eukaryotes." • Explain how differential gene expression leads to programs of cellular specialisation." " Biol115_2014_Lecture 11" 3" Eukaryotic gene expression is regulated at many stages" • All organisms must regulate which genes are expressed at any given time" • In multicellular organisms regulation of gene expression is essential for cell specialisation." Biol115_2014_Lecture 11" 4" Chromosome packaging and gene expression" Non-coding RNA (e.g. siRNA) can convert euchromatin into non-expressed heterochromatin." Biol115_2014_Lecture 11" 5" Differential Gene Expression" • Almost all the cells in an organism are genetically identical" • Differences between cell types result from differential gene expression, the expression of different genes by cells with the same genome" • Gene expression is regulated at many stages" Biol115_2014_Lecture 11" 6" Regulation of Transcription Initiation" • Associated with most eukaryotic genes are multiple control elements, segments of noncoding DNA that serve as binding sites for transcription factors that help regulate transcription" • Control elements and the transcription factors they bind are critical to the precise regulation of gene expression in different cell types" Biol115_2014_Lecture 11" 7" Enhancers and Specific Transcription Factors" • Proximal control elements are located close to the promoter" • Distal control elements, groupings of which are called enhancers, may be far away from a gene or even located in an intron" Biol115_2014_Lecture 11" 8" The Roles of Transcription Factors" To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors! Biol115_2014_Lecture 11" 9" • An activator is a transcription factor that binds to an enhancer and stimulates transcription of a gene" • Some transcription factors function as repressors, inhibiting expression of a particular gene by a variety of methods" Biol115_2014_Lecture 11" 10" Enhancer (distal control elements)" Proximal control elements" Transcription start site" DNA" Upstream" Exon" Intron" Exon" Exon" Downstream" Poly-A signal" Intron" Exon" Intron" Exon" Cleaved 3ʹ′ end of primary RNA processing" transcript" Promoter" Primary RNA transcript 5ʹ′" (pre-mRNA)" Poly-A Transcription signal sequence" termination region" Intron" Exon" Transcription" Intron RNA" Coding segment" mRNA"G" P" P" P" Start Stop 5ʹ′ Cap" 5ʹ′ UTR" codon" codon" Biol115_2014_Lecture 11" AAA ⋅⋅⋅ AAA" 3ʹ′" 3ʹ′ UTR" Poly-A tail" 11" Promoter" Activators" DNA" Enhancer" Distal control element" TATA box" DNA- bending protein" Gene" General transcription factors" Group of mediator proteins" RNA polymerase II" RNA polymerase II" Transcription initiation complex" Biol115_2014_Lecture 11" RNA synthesis" 12" The language of regulation" Eukaryotic Regulatory elements" Promoters" Binding sites for RNA polymerase" Control elements: proximal, distal" Function: enhancers, repressors (or suppressors)" Biol115_2014_Lecture 11" Bound by: transcription factors (called activators or suppressors)" 13" Combinatorial Control of Gene Activation" A particular combination of control elements can activate transcription only when the appropriate activator proteins are present" Biol115_2014_Lecture 11" 14" Enhancer" Control elements" Promoter" Albumin gene" LIVER CELL NUCLEUS" Crystallin LENS CELL gene" NUCLEUS" Available activators" Available activators" Albumin gene expressed" Crystallin gene not expressed" (a) Liver cell" Biol115_2014_Lecture 11" Albumin gene not expressed" Crystallin gene expressed" (b) Lens cell" 15" Coordinately Controlled Genes in Eukaryotes" • Unlike the genes of a prokaryotic operon, each of the co-expressed eukaryotic genes has a promoter and control elements" • These genes can be scattered over different chromosomes, but each has the same combination of control elements" • Copies of the activators recognise specific control elements and promote simultaneous transcription of the genes" Biol115_2014_Lecture 11" 16" Coordinate expression of antimicrobial peptide genes" chromosome 1" Rel site" gene 1 (cecropin)! Rel site" chromosome 2" gene 2! (diptericin)! gene 3 ! (drosomycin)! Rel site" Rel is a control element that regulates the expression of antimicrobial peptide genes" Biol115_2014_Lecture 11" 17" A program of differential gene expression leads to the different cell types in a multicellular organism" • During embryonic development, a fertilised egg gives rise to many different cell types" • Cell types are organised successively into tissues, organs, organ systems, and the whole organism" • Gene expression orchestrates the developmental programs of animals" Biol115_2014_Lecture 11" 18" • Cell differentiation is the process by which cells become specialised in structure and function" • Differential gene expression results from genes being regulated differently in each cell type" Biol115_2014_Lecture 11" 19" Sequential Regulation of Gene Expression During Cellular Differentiation" • Determination commits a cell to its final fate" • Determination precedes differentiation" • Cell differentiation is marked by the production of tissue-specific proteins" Biol115_2014_Lecture 11" 20" • Myoblasts produce muscle-specific proteins and form skeletal muscle cells " • MyoD is one of several “master regulatory genes” that produce proteins that commit the cell to becoming skeletal muscle" • The MyoD protein is a transcription factor that binds to enhancers of various target genes" Biol115_2014_Lecture 11" 21" Master regulatory gene myoD! Nucleus" Embryonic precursor cell" Other muscle-specific genes" DNA" OFF" OFF" mRNA" OFF" Myoblast (determined)" MyoD protein (transcription factor)" mRNA" Part of a muscle fibre (fully differentiated cell)" MyoD" mRNA" Another transcription factor" Biol115_2014_Lecture 11" mRNA" mRNA" Myosin, other muscle proteins, and cell cycle– blocking proteins" 22" Stem Cells of Animals " • A stem cell is a relatively unspecialised cell that can reproduce itself indefinitely and differentiate into specialised cells of one or more types" • Stem cells isolated from early embryos at the blastocyst stage are called embryonic stem cells; these are able to differentiate into all cell types" • The adult body also has stem cells, which replace non-reproducing specialised cells" Biol115_2014_Lecture 11" 23" Totipotent stem cells: obtained from early embryos, spores and plant calluses – can give rise to to a complete individual" " Pluripotent stem cell: can give rise to many different cell types, but cannot produce an entire individual." " Multipotent stem cell:" Gives rise to different cell types within tissues." Biol115_2014_Lecture 11" 24" Induced pluripotent stem cells (iPS) can used to treat a repair of damaged tissues in adults" Biol115_2014_Lecture 11" 25" You should now be able to:" • Explain the role of promoters, enhancers, activators and repressors in transcriptional control." • Explain how eukaryotic genes can be coordinately controlled." • Describe how cells are instructed to express genes at the appropriate time." • Explain how cellular differentiation occurs at the cellular level." Biol115_2014_Lecture 11" 26"