Human Genome

Chapter 18: Regulation of Gene ExpressionEssential Knowledge2.e.1 Timing and coordination of specific events are necessary for the normal development of an organism, and these events are regulated by a variety of mechanisms (18.2-18.4).3.b.1 Gene regulation results in differential gene expression, leading to cell specialization (18.1-18.3).3.b.2 A variety of intercellular and intracellular signal transmissions mediate gene expression (18.1-18.4).4.a.3 Interactions between external stimuli and regulated gene expression result in specialization of cells, tissues, and organs (18.4).Bacterial Regulation of TranscriptionSome bacteria can regulate their gene expression based on their surroundingsE. coli needs tryptophan to survive; if it isnt getting trp from its environment (such as the human colon), then it makes its ownWhen the host is ingesting enough trp for the E. coli, the bacteria inhibits enzyme activity thereby shutting down the synthesis of trp and conserving energy.OperonsFig. 18.2, page 352An operon includes the operator (which controls the access of RNA polymerase to the genes), the promoter (a site where RNA polymerase can bind to DNA and begin transcription), and all the genes they controlOperon FunctionUsing trp synthesis as an example:The trp operon is turned on meaning that RNA polymerase can bind to the promoter and transcribe the genes of the operonThe trp repressor switches the operon off, and the repressor binds to the operator blocking attachment of RNA polymerase to the promoter preventing gene transcriptionFig. 18.3, page 353Human Genome3 billion base pairs~30,000 genesTotal of almost 3 FEET of DNA in each and every cell in our bodies

Questions?With so much DNA in a cell, how is it organized or packaged?How is the expression of the DNA controlled?Microscopic Levels1. Nucleosomes2. Chromatin Fibers3. Looped Domains4. Chromosomes

Focus on #1 & #4

Nucleosomes"Beads on a StringDNA wound on a protein corePackaging for DNAControls transcription

Protein CoreTwo molecules of four types of Histone proteinsH1- 5th type of Histone protein attaches the DNA to the outside of the coreChromosomesLarge units of DNA/chromatin/proteinsAppear only during cell division (after Interphase)Similar to "Chapters" in the Book of Life

Chromosome Regions1. Heterochromatin - highly condensed chromatin; areas that are not transcribed2. Euchromatin - less condensed chromatin; areas of active transcription

Molecular Level Organization1. Repetitive Sequences2. Satellite DNA3. Interspersed Repetitive DNA4. Multigene FamiliesResultGive regions of the DNA different densitiesLinked to some genetic disorders.Ex. - Fragile X SyndromeHuntingtons diseaseMultigene FamiliesA collection of identical or very similar genesFrom a common ancestral gene.May be clustered or dispersed in the genomeIdentical FamiliesIdentical genes for the same proteinEx: Ribosomal Protein and rRNAResult - Many copies of ribosomes possibleMost common gene in DNANonidentical FamiliesRelated clusters of genes that are nearly identical in their base sequences.Ex: Globin GenesPseudogeneGene with sequences very similar to real genes, but lack promoter sitesAre not transcribed into proteinsPossible proof of transpositions?Genome PlasticityChanges in the ways a gene can be expressedSeen only in somatic cellsHave major effects on gene expression within particular cells and tissuesTypes of Expression1. Gene Amplification2. Selective Gene Loss3. Genomic Rearrangements1. Gene AmplificationThe selective replication of certain genesEx: rRNA genes in eggsResult - many copies of rRNA for making ribosomes

2. Selective Gene LossLoss of genes or chromosomes in some tissues during developmentResult - DNA (genes) lost and not expressed3. Genomic RearrangementsShuffling of DNA areas (not from meiosis)Ex: Transposons retrotransposons antibody genesExamples of Transposons: flower petals

Control of Gene ExpressionComplicated ProcessMany levels of control are possibleHint - students should understand several mechanisms of control (see slides to follow)Main Control Levels1. Nucleus - those inside the nuclear membrane2. Cytoplasm - those that occur in the cytoplasm

Nucleus Level1. Extra-Cellular Signals (Chapter 11 Cell communication)2. Chromatin Modifications3. Transcriptional Control4. Posttranscriptional ControlChromatin ModificationsDNA MethylationHistone AcetylationGene rearrangementsGene amplificationDNA MethylationAddition of methyl groups (-CH3) to DNA basesResult - long-term shut-down of DNA transcriptionEx: Barr bodiesHistone AcetylationAttachment of acetyl groups (-COCH3) to AAs in histonesResult - DNA held less tightly to the nucleosomes, more accessible for transcriptionTranscriptional ControlEx: EnhancersAreas of DNA that increase transcription.Ex: DNA-Binding DomainsProteins that bind to DNA and regulate transcription Ex: regulatory RNA.Small RNA molecules that are not translatedUsually interact with DNAResult - genes are more (or less) available for transcription.

Posttranscriptional Control1. RNA Processing Ex - introns and exons2. RNA Transport moving the mRNA into the cytoplasm3. RNA Degradation breaking down old mRNACytoplasm Level of Control1. Translation2. Polypeptide ChangesTranslation ControlRegulated by the availability of initiation factorsAvailability of tRNAs, AAs and other protein synthesis factors (Review Chapter 17)Polypeptide ChangesChanges to the protein structure after translationEx: CleavageModificationsActivationTransportDegradationGene Expression and CancerCancer - loss of the genetic control of cell divisionBalance between growth-stimulating pathway (accelerator) and growth-inhibiting pathway (brakes)

Proto-oncogenesNormal genes for cell growth and cell division factorsGenetic changes may turn them into oncogenes (cancer genes)Ex: Gene Amplification, Translocations, Transpositions, Point MutationsTumor-Suppressor GenesGenes that inhibit cell divisionEx - p53, p21Cancer ExamplesRAS - a G proteinWhen mutated, causes an increase in cell division by over-stimulating protein kinasesSeveral mutations knownCancer Examplesp53 - involved with several DNA repair genes and checking genes.When damaged (e.g. cigarette smoke), cant inhibit cell division or cause damaged cells to apoptose.CarcinogensAgents that cause cancerEx: radiation, chemicalsMost work by altering the DNA, or interfering with control or repair mechanismsSee Chapter 17 for more on this!Multiple Hit HypothesisCancer is the result of several control mechanisms breaking downEx: Colorectal Cancer requires 4 to 5 mutations before cancer startsColorectal Cancer

SummaryRecognize the operon model for gene regulation in prokaryotes.Identify different mechanisms of eukaryotic gene expression control.Recognize the roles of RNA in controlling gene expression.Recognize examples of differential gene expression in multicellular organisms.Recognize that cancer is caused by changes in gene regulation.