gene_regulation_lecture_1.pdf

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1. Gene Regulation Lecture I Seth Brown, Ph.D. Department of Internal Medicine The University of Iowa April 11, 2012
2. How is biological complexity achieved? An Elaborate Engineering Problem: 50e12 human cells! • Environmental Adaptation climate (sun), diet (lactose), etc. • Diverse physiological I/O hormonal responses (estrogen), etc. • Coordinated communication atoms → cells → ecosystems • Robustness fault-tolerance, redundancy, repair, etc. Gene Regulation , Lecture I Introduction 2 / 17
3. Complexity is achieved via gene regulation Gene Regulation , Lecture I Introduction 3 / 17
4. Regulation is complex Gene Regulation , Lecture I Introduction 4 / 17
5. The molecules of gene expression Gene Regulation , Lecture I Introduction 5 / 17
6. The central dogma of gene expression Gene Regulation , Lecture I Introduction 6 / 17
7. A simplified regulatory response Gene Regulation , Lecture I Introduction 7 / 17
8. Central mechanisms in gene regulation DNA RNA transcript mRNA protein inactive protein inactive mRNA Nucleus Cytosol transcriptional control 1 2 RNA processing control 3 RNA transport & localization control 5 6 4 translational control protein activity control mRNA degradation control Gene Regulation , Lecture I Introduction 8 / 17
9. Common themes in gene regulation . . 1 Allosteric regulation Regulation of a protein by binding of an effector molecular to a region of the protein other than the active site. . . 2 Chromatin structure Chromatin structure changes make the DNA template more accessible for assembly of regulatory factors. . . 3 Affinity High affinity negative regulatory proteins block accessability of an activator to its target. . . 4 Post-translational modifications Covalent modifications can alter protein function. Gene Regulation , Lecture I Introduction 9 / 17
10. Allosteric regulation • Allostery can lead to positive and negative feedback loops • Ubiquitious regulatory mechanism in transcription and translation Gene Regulation , Lecture I Transcription & Chromatin Regulation 10 / 17
11. Overview of transcription Gene Regulation , Lecture I Transcription & Chromatin Regulation 11 / 17
12. Eukaryotic regulatory complexity • Enhancers function to increase the P(activation) • Silencers can block activator function, control core transcription machinery, or alter chromatin structure Important concept: The interplay of numerous regulatory mechanisms govern the final level of gene product synthesis Gene Regulation , Lecture I Transcription & Chromatin Regulation 12 / 17
13. Chromatin structure and dynamics • Basic structure Nucleosome Beads-on-a-string 30nm fiber Solenoids Chromosomes • Dynamics/Regulation Compaction & accessibility Histone modifications Nuclear attachment regions Gene Regulation , Lecture I Transcription & Chromatin Regulation 13 / 17
14. Nucleosomes • A nucleosome is composed of a histone octamer of: 2x: (H2A, H2B, H3, & H4 histones) • Variant histones such as macroH2A can be substituted into nucleosomes → altered function(s) • Histone tails serve as post-translational modification sites, which can impact gene regulation... Gene Regulation , Lecture I Transcription & Chromatin Regulation 14 / 17
15. H3 & H4 covalent tail modifications Gene Regulation , Lecture I Transcription & Chromatin Regulation 15 / 17
16. 3 classes of chromatin modifying factors Important points about chromatin modifiers: • Histone tails act as scaffolds to recruit chromatin modifiers, which potentate gene regulatory changes • Specific modifications selectively recruit different writers, erasers, readers, and other factors • Different tail modifications "influence" other modifications Gene Regulation , Lecture I Transcription & Chromatin Regulation 16 / 17
17. Transcription & chromatin Transcription and chromatin regulation are tightly coupled • Chromatin modifying factors are recruited by RNAP/TFs to alter chromatin structure • Chromatin can alter the ability of RNAP/TFs to bind and transcribe genes Gene Regulation , Lecture I Transcription & Chromatin Regulation 17 / 17