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Overview: How Eukaryotic Genomes Work and Evolve • Two features of eukaryotic genomes are a major information-processing challenge: – First, the typical eukaryotic genome is much larger than that of a prokaryotic cell - can impact efficiency of gene expression – Second, cell specialization limits the expression of many genes to specific cells Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 19.1: Chromatin structure is based on successive levels of DNA packing • Eukaryotic DNA is precisely combined with a large amount of protein • The DNA-protein complex, called chromatin, is ordered into higher structural levels than the DNAprotein complex in prokaryotes • Eukaryotic chromosomes contain an enormous amount of DNA relative to their condensed length Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Nucleosomes, or “Beads on a String” • Proteins called histones are responsible for the first level of DNA packing in chromatin • The association of DNA and histones seems to remain intact throughout the cell cycle • In electron micrographs, unfolded chromatin has the appearance of beads on a string • Each “bead” is a nucleosome, the basic unit of DNA packing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2a 2 nm DNA double helix Histones Histone tails Histone H1 Linker DNA (“string”) Nucleosome (“bead”) Nucleosomes (10-nm fiber) 10 nm Higher Levels of DNA Packing • The next level of packing forms the 30-nm chromatin fiber • Interactions between histone tails, linker DNA, and other nucleosomes cause the 10-nm fiber to coil and fold, forming a chromatin fiber approximately 30 nm in diameter Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2b 30 nm Nucleosome 30-nm fiber • In turn, the 30-nm fiber forms looped domains, making up a 300-nm fiber • During prophase of mitosis or meiosis, the 30-nm fiber forms looped domains by attaching to a nonhistone protein scaffold, giving rise to a 300-nm fiber Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2c Protein scaffold Loops 300 nm Looped domains (300-nm fiber) Scaffold • In a mitotic chromosome, the 300-nm looped domains coil and fold, forming the metaphase chromosome Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-2d 700 nm 1,400 nm Metaphase chromosome • Interphase chromatin is usually much less condensed than that of mitotic chromosomes • Much of the interphase chromatin is present as a 10-nm fiber, and some is 30-nm fiber, which in some regions is folded into looped domains • Interphase chromosomes have highly condensed areas, called heterochromatin, and less compacted areas, called euchromatin Animation: DNA Packing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 19.2: Gene expression can be regulated at any stage, but the key step is transcription • All organisms must regulate which genes are expressed at any given time • A multicellular organism’s cells undergo cell differentiation which is a specialization in form and function Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Differential Gene Expression • Differences between cell types result from differential gene expression, the expression of different genes by cells possessing the same genome • In each type of differentiated cell, a unique subset of genes is expressed • Many key stages of gene expression can be regulated in eukaryotic cells Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-3 Signal NUCLEUS Chromatin Chromatin modification DNA Gene available for transcription Gene Transcription RNA Exon Primary transcript Intro RNA processing Tail Cap mRNA in nucleus Transport to cytoplasm CYTOPLASM mRNA in cytoplasm Degradation of mRNA Translation Polypeptide Cleavage Chemical modification Transport to cellular destination Active protein Degradation of protein Degraded protein Check-points where gene expression can be regulated Regulation of Chromatin Structure • Genes within highly packed heterochromatin are usually not expressed • Chemical modifications to histones and DNA of chromatin influence both chromatin structure and gene expression Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Histone Modification • In histone acetylation, acetyl groups are attached to positively charged lysines in histone tails • This process seems to loosen chromatin structure, thereby promoting the initiation of transcription Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-4 Histone tails DNA double helix Amino acids available for chemical modification Histone tails protrude outward from a nucleosome Unacetylated histones Acetylated histones Acetylation of histone tails promotes loose chromatin structure that permits transcription DNA Methylation • DNA methylation, the addition of methyl groups to certain bases in DNA, is associated with reduced transcription in some species • In some species, DNA methylation causes longterm inactivation of genes in cellular differentiation Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Regulation of Transcription Initiation • Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Organization of a Typical Eukaryotic Gene • Associated with most eukaryotic genes are control elements, segments of noncoding DNA that help regulate transcription by binding certain proteins • Control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types • Control elements are loosely analogous (similar in concept) to the operator of the prokaryotic operon in that binding of certain factors will influence the levels of transcription Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-5 Enhancer (distal control elements) Proximal control elements Exon Intron Exon Poly-A signal Termination sequence region Intron Exon DNA Upstream Downstream Promoter Primary RNA transcript 5 (pre-mRNA) Transcription Exon Intron Intron RNA Poly-A signal Exon Intron Exon Cleaved 3 end of primary transcript RNA processing: Cap and tail added; introns excised and exons spliced together Coding segment mRNA 3 5 Cap 5 UTR (untranslated region) Start codon Stop codon Poly-A 3 UTR (untranslated tail region) The Roles of Transcription Factors • To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors • General transcription factors are essential for the transcription of all protein-coding genes • In eukaryotes, high levels of transcription of particular genes depend on control elements interacting with specific transcription factors Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Enhancers and Specific Transcription Factors • Proximal control elements are located close to the promoter • Distal control elements, groups of which are called enhancers, may be far away from a gene or even in an intron • An activator is a protein that binds to an enhancer and stimulates transcription of a gene Animation: Initiation of Transcription Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-6 Distal control element Activators Promoter Gene DNA TATA box Enhancer transcription factors DNA-bending protein Group of mediator proteins RNA polymerase II RNA polymerase II Transcription Initiation complex RNA synthesis • Some transcription factors function as repressors, inhibiting expression of a particular gene • Some activators and repressors act indirectly by influencing chromatin structure - recruiting proteins that will affect levels of histone acetylation: Will activators tend to recruit proteins that acetylate or de-acetylate histone? What about repressors? Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-7 Liver cell nucleus Available activators Enhancer Control elements Lens cell nucleus Available activators Promoter Albumin gene Crystallin gene Albumin gene not expressed Albumin gene expressed Crystallin gene not expressed Liver cell Crystallin gene expressed Lens cell Coordinately Controlled Genes • Unlike the genes of a prokaryotic operon, coordinately controlled eukaryotic genes each have a promoter and control elements • The same regulatory sequences are common to all the genes of a group, enabling recognition by the same specific transcription factors Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Mechanisms of Post-Transcriptional Regulation • Transcription alone does not account for gene expression • More and more examples are being found of regulatory mechanisms that operate at various stages after transcription • Such post-transcriptional mechanisms allow a cell to fine-tune gene expression rapidly in response to environmental changes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings RNA Processing • In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns Animation: RNA Processing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-8 Exons DNA Primary RNA transcript RNA splicing mRNA or mRNA Degradation • The life span of mRNA molecules in the cytoplasm is a key to determining the protein synthesis • The mRNA life span is determined in part by sequences in the leader and trailer regions Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Initiation of Translation • The initiation of translation of selected mRNAs can be blocked by regulatory proteins that bind to sequences or structures of the mRNA, usually found in either the 5´ or 3´ UTR • Additionally, a poly-A tail of insufficient length can inhibit efficient translation of a transcript • Alternatively, translation of all mRNAs in a cell may be regulated simultaneously by mass activation or inactivation of translation initiation factors Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Protein Processing and Degradation • After translation, various types of protein processing, including cleavage and the addition of chemical groups (such as phosphate groups), are subject to control • Proteasomes are giant protein complexes that bind protein molecules and degrade them Animation: Protein Processing Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings LE 19-10 Proteasome and ubiquitin to be recycled Ubiquitin Proteasome Protein to be degraded Ubiquitinated protein Protein entering a proteasome Animation: Protein Degradation Protein fragments (peptides)