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  1. Chapter 19Eukaryotic genomes: organization, regulation and evolution“The Inner life of the Cell”

  2. Gene expression… • Is altered in response to environmental changes, both internal and external • Is influenced by the structure of chromatin • Heterochromatin is highly compacted and is not transcribed • Euchromatin is less compacted and available for transcription • Is most often regulated at the transcription stage • Differential gene expression (cell differentiation) is the result of genes being turned “on” or “off” in different cells having the same genome • Only 1.5% of human DNA codes for proteins

  3. Chromatin structure…. • Eukaryotic DNA associates with many histone proteins that form complex structures – the mass of histones = the mass of DNA • Histones – highly conserved, small, basic proteins that shape the 1st level of chromatin structure: • The high [ ]’s of arganine and lysine make them +ly charged • Of the 5 types (H1,H2A,H2B,H3,H4) all but H1 are found in the nucleosome, the basic unit of DNA packing • Are evolutionarily conserved • Only leave DNA briefly during replication • Interphase chromatin is attached to the nuclear lamina to keep chromosomes from tangling

  4. Eukaryotic DNA structure DNA + histones form nucleosomes (10nm fiber) Nucleosomes coil to form chromatin fiber (30nm fiber) 30nm fiber folds into looped domains (300nm fiber) Chromatin condenses further to form the metaphase chromosome (highly compacted 1400 nm)

  5. CONTROL POINTS in eukaryotic gene expression: • Regulation of chromatin structure: histone acetylation and DNA methylation • Transcription of the gene: transcription initiation • RNA Processing: alternative RNA splicing • mRNA export: • mRNA degradation: polyA tail, miRNA, RNAi • Translation of mRNA: regulatory proteins block initiation of translation • Polypeptide processing: cleavage, modification and transport • Protein Degradation: ubiquitin/proteasome activity

  6. Stages in which eukaryotic gene expression can be regulated are represented by the colored boxes

  7. Histone modification – acetyl groups added to histone tails relax chromatin and promote transcription DNA methylation can inactivate genes and be inherited by offspring– genomic imprinting works this way! Regulation of chromatin structure:

  8. Control of gene expression in eukaryotes: an overview •

  9. The eukaryotic gene consists of • the gene + RNA polymerase + a promoter • Control elements – non-coding DNA that regulates transcription by binding to certain proteins. Distal elements called enhancers are very important • Transcription factors: • General transcription factors result in low RNA production • Specific transcription factors can promote high levels of transcription. They may be: • Activators – protein that stimulates transcription • Repressors – proteins that inhibit gene expression • Activators and repressors may alter chromatin structure, thereby further influencing gene expression

  10. Transcription of the gene: regulation of initiation

  11. Prokaryotes have operons to control expression of genes with related functions…what about eukaryotes? • Functionally related eukaryotic genes are co-expressed because they have the same control elements that are activated by the same chemical signals

  12. Regulation of transcription •

  13. Alternative RNA splicing can generate different mRNA molecules from the same primary transcript – organisms can produce more than 1 polypeptide from a single gene! RNA processing:

  14. The mRNA transcript:

  15. mRNA degradation: • Eukaryotic mRNA can have a survival time measured in weeks…how is it degraded? • Shortening of the poly-A tail and removal of the 5’cap allows nucleases to degrade mRNA • microRNA’s can degrade mRNA or block its translation (called RNA interference)

  16. mRNA degradation:

  17. mRNA translation • Initiation of translation can be blocked by regulatory proteins that bind to the UTR’s and block the attachment of ribosomes to the mRNA

  18. Polypeptide processing: • Any interference in the processing of the polypeptide can alter gene expression. Polypeptides are processed via • Cleavage • Chemical modifications • Protein transport to its target destination

  19. Degradation of protein: • The lifespan of a protein varies and is strictly regulated by other proteins • Proteins tagged with ubiquitin are recognized by proteosomes and degraded

  20. Protein degradation:

  21. A review of gene expression: prokaryotes vs eukaryotes •

  22. Small genome, no specialization Most of their DNA codes for protein or RNA’s, very little “junk” Genome = DNA + few proteins in simple arrangement RNA processing not an option for controlling gene expression mRNA has a short life span (minutes) Both alter gene expression in response to environment; in both, transcription initiation is the most important control point Larger genome, cell specialization Most of the DNA does not code for protein or RNA’s Genome = DNA w/many proteins in complex arrangement RNA processing allows for several opportunities to regulate genes mRNA is long lived (days to months) Gene expression:prokaryotic eukaryotic

  23. Cancer results from genetic changes that affect cell cycle control • It is a disease in which cells escape control methods that normally regulate cell growth and division • The agents of change can be random spontaneous mutations or carcinogens • Cancer-causing genes, oncogenes, were originally discovered in retroviruses

  24. Proto-oncogenes: • Proto-oncogenes code for proteins that stimulate normal cell growth and division They may turn into oncogenes by: • Translocation/transposition within the genome • Gene amplification • Point mutations within a control element or the gene that may lead to a protein that is more active or longer lived

  25. Proto-oncogenes

  26. Tumor-suppressor genes • Tumor-suppressor genes encode for proteins that help prevent uncontrolled cell division. They may function to: • Repair damaged DNA • Control cell adhesion • Act as components of cell-signaling pathways that inhibit the cell cycle • A mutation in a tumor suppressor gene reduces the activity of its protein product, leads to excessive cell division and potentially cancer

  27. The Ras proto-oncogene (G protein) is part of a cell cycle stimulating pathway. A mutation making this pathway abnormally active could result in cancer Some proteins encoded by proto-oncogenes and tumor-suppressor genes are components of cell signaling pathways

  28. The product of the p53 gene (p53 protein) inhibits the cell cycle and allows time for DNA repair mechanisms to operate. Deficiencies in this cell cycle inhibiting pathway could promote cancer

  29. Control of the cell cycle: p53 and rb •

  30. The multistep model for cancer development: • Cancer results from an accumulation of mutations, not just one • Usually there is the presence of one active oncogene and the mutation of several tumor-suppressor genes • Certain viruses can promote cancer by insertion of viral DNA into a cells genome • Individuals who inherit a mutant oncogene or tumor-suppressor allele have an increased risk of developing cancer

  31. Eukaryotic genomes have many noncoding DNA sequences in addition to genes • Eukaryotes have fewer genes/DNA length than do prokaryotese • Most of the DNA is noncoding (98.5%) • Most intergenic DNA is repetitive DNA in the form of transposable elements and related sequences (44%) • There are 2 types of transposable elements: • Transposons and retrotransposons

  32. Transposons: Move within a genome via a DNA intermediate Can move via: Cut-and-paste methods Copy and paste methods Retrotransposons: Move within a genome via an RNA intermediate This is the most prevalent type Transposable elements:

  33. Simple sequence DNA • Short, noncoding DNA sequences • Tandemly repeated • Prominent in centromeres and telomeres • Play a structural role in the chromosome

  34. Multigene families: • Collections of identical or very similar genes, • A multigene family is a member of a family of related proteins encoded by a set of similar genes. Multigene families are believed to have arisen by duplication and variation of a single ancestral gene. Examples of multigene families include those that encode the actins, hemoglobins, immunoglobulins, and histones.

  35. The evolution of the Genome - a history of mutation! • Polyploidy! A duplication of chromosome sets. One set functions normally, the other is free to diverge • Duplication of individual DNA segments or genes which may then diverge to create new genes and gene products • Rearrangement of gene parts: • Exon duplication • Exon shuffling • The use of transposable elements that promote recombination, disrupt genes, or carry genes to new locations also contributes to genome evolution