Transcript Slide 1
Eukaryotic Gene Regulation Chapter 18 Overview Eukaryotes can regulate gene expression at multiple stages from gene to functional protein Regulation of chromatin structure DNA methylation Transcription initiation factors Alternative RNA processing Protein degradation Slide 2 of 25 -- blue = DNA -- orange = RNA -- purple = protein --Each of these is a possible site for regulation, but not all are used in any instance or cell Slide 3 of 25 How do we get different cell types? Red blood cells, muscle cells, neurons… Every cell has the same genes Different cells express only a fraction of their genes 20% of cell’s genes are expressed Slide 4 of 25 Histone Acetylation -- DNA level of regulation -- Histone proteins have protruding “tails” -- Acetyl groups can be added to these tails -- Acetylated histones lose their + charge, and are unable to bind to other nucleosomes -- Acetylated histones = transcription more likely Slide 5 of 25 Histone Code Hypothesis Histone tails can be Acetylated, methylated, or phosphorylated Methylation = condensation of chromatin Phosphorylation = separation of histones So which determines the proteins produced: acetylation or the specific combination of these modifications? Slide 6 of 25 DNA Methylation DNA itself can be methylated as well Actually methyl groups are attached to the nitrogenous bases of nucleotides Specifically cytosine Methylated bases are not able to be expressed Remember methylation from Inactivated X chromosomes? Interfere with normal methylation = weird results Slide 7 of 25 Important Difference… Histone acetylation = INCREASED transcription DNA methylation = DECREASED transcription Slide 8 of 25 Why are identical twins different? They have the same genome, so WTF? Base-pair mutations are one way to get genetic diversity Different DNA sequences may be methylated, this results in certain sequences being turned off So same DNA but phenotypic variation Identical twins, but one has schizophrenia while the other does not Called epigenetic inheritance (traits that are NOT contained on nucleotide sequences) Slide 9 of 25 Transcriptional Modification Most important area of regulation or control of gene expression Was this true in prokaryotes? Involves Enhancer regions on the DNA Activator proteins bind to mediator proteins The complex is called transcription initiation complex Transcription of the downstream regions is enhanced Slide 10 of 25 Slide 11 of 25 -- Activator proteins bind to the enhancer region of DNA -- Activator proteins also bind to Mediator proteins + Transcription factors -- Forms transcription initiation complex -- Almost guarantees that the gene will be expressed Slide 12 of 25 -- Activator proteins bind to enhancer DNA region -- Different activator proteins = different gene transcribed & expressed -- Activator proteins = directors of transcription in eukaryotes Slide 13 of 25 Alternative RNA Splicing -- Spliceosomes can splice the primary RNA transcript differently -- Creates different proteins -- Fruit fly gene = 38,000 different combinations of proteins -- Yet again, is phenotypic variation due to genetic sequences? Slide 14 of 25 siRNA Cure for Ebola? 1.5% of genome codes for proteins Even smaller amount codes for RNAs (tRNA, mRNA, rRNA) So is any part of the 98% ever transcribed? Slide 15 of 25 Slide 16 of 25 miRNA microRNAs are capable of binding complementary sequences in mRNA molecules Usually degrades the mRNA it binds OR blocks translation of the mRNA 1/3 of all genes regulated via miRNAs Slide 17 of 25 RNA Interference (RNAi) Inject dsRNA molecules into a cell This turns off gene expression of those genes with same sequence as the dsRNA Small Interfering RNA (siRNA) were the dsRNA responsible for the interference How did this lead to a treatment for Ebola? Ebola is an RNA based virus What about HIV? Hepatitis A or C? common cold? Dengue fever? influenza? H1N1, H5N1? Slide 18 of 25 Skip 18.4 Slide 19 of 25 Cancer Genes Oncogenes = cancer-causing genes Proto-oncogenes = genes that codes for proteins that promote normal cell growth Proto-oncogenes can become oncogenes Leads to an increase in protein production OR an increase in the activity of normal protein production Either leads to TOO MUCH mitosis Slide 20 of 25 Tumor-Suppressor Genes The produced proteins inhibit cell division If a mutation decreases production of these products, cell division will accelerate 2 ways to get neoplastic growths (cancer): Mutation which alters proto-oncogenes into oncogenes Over-produces protein OR hyperactive protein production This interferes with usual mechanism of cell cycle regulation Mutation interferes with tumor-suppressor genes Insufficient production leads to mitotic hyperactivity Slide 21 of 25 Again… Slide 22 of 25 Cell Cycle Stimulator Pathway Mutation in ras? -- Activity even though no growth factor has been received by the RTK -- Outcome = Excessive Mitosis Slide 23 of 25 p53 gene -- Commonly called the “guardian angel of the genome” -- Halts cell cycle by binding CdK proteins -- Allows time for DNA repair --p53 is also directly involved in DNA repair --p53 initiates apoptosis if DNA damage is beyond repair Slide 24 of 25 MultiStep Model of the Development of Colorectal Cancer Slide 25 of 25