Gene Regulation Lecture Outline - A01-2024 PDF

REGULATION OF GENE EXPRESSION IN EUKARYOTES Relevant reading: Morris text, 4th ed., Chapters 17 & 18 (applicable sections only) The human body -200 major cell types -all share same genome -but, look and function differently from one another Each cell type express...

REGULATION OF GENE EXPRESSION IN EUKARYOTES Relevant reading: Morris text, 4th ed., Chapters 17 & 18 (applicable sections only) The human body -200 major cell types -all share same genome -but, look and function differently from one another Each cell type expresses different sets of genes  EUKARYOTIC GENE REGULATION -how cells control gene expression -can occur at many levels We will consider: 1. Epigenetic control 2. Transcriptional control 3. Translational control  CHROMATIN REMODELING DNA in chromatin is inaccessible to the transcription machinery until it is remodeled. -When chromatin is tightly coiled, transcription factors and enzymes have no access to promoters or enhancers on the DNA. Chemical modification of histone tails repositions nucleosomes and exposes stretches of DNA to the transcription machinery. -Occurs during development and in response to environmental cues.  HISTONE TAIL MODIFICATIONS Pattern of modifications = histone code = affects chromatin structure and gene transcription. METHYLATION OF DNA  METHYLATION OF DNA Chemical modification of DNA can also regulate gene expression -methylation of cytosines (on CG clusters close to a promoter of a gene) -can recruit proteins that remodel chromatin, modify histone tails etc.  EPIGENETIC EFFECTS = changes that are not made in the DNA sequence itself, but to the manner in which the DNA is packaged, sometimes causing changes in gene expression. These changes can be inherited but are often reversible and responsive to changes in the environment. http://www.mdpi.com/1424-8247/6/1/1/htm http://www.nature.com/nrn/journal/v15/n12/images/nrn3839-i1.jpg DEVELOPMENT A fertilized human egg is totipotent = can give rise to all OF AN EMBRYO cell types in a complete organism + extraembryonic structures + placental cells The cells of the inner cell mass are embryonic stem cells and are pluripotent = can give rise to any of cell of the body. Cells of the germ layers are multipotent = these cells can form a limited number of types of specialized cells. Totipotent, pluripotent, and multipotent cells are all stem cells = cells that are capable of differentiating into different cell types. Genes are silenced as cells differentiate - Can they be re-activated? - Can we go from a differentiated cell back to a stem cell? http://www.nature.com/nsmb/journal/v19/n12/images/nsmb.2449-F7.jpg INDUCED PLURIPOTENT STEM (iPS) CELLS AS THERAPY http://www.eurostemcell.org/files/images/iPS_factsheet_diag_new_Dec2012.img_assist_custom-600x452.png REGULATION OF AN ENTIRE CHROMOSOME REGULATION OF AN ENTIRE CHROMOSOME X-INACTIVATION X-INACTIVATION TRANSCRIPTIONAL CONTROL REGULATORY TRANSCRIPTION FACTORS Enhance or Silencer sequences Activator or Repressor proteins http://ib.bioninja.com.au/_Media/enhancer-silencer_med.jpeg  TRANSLATIONAL REGULATION: SMALL REGULATORY RNAs e.g. siRNAs, miRNAs. Chapter 17 Active Lecture Slide 30 Small Regulatory RNA: siRNA When siRNAs pair with a target mRNA, there are no mismatches. The perfect match between the siRNA and the target mRNA results in RISC degrading the target mRNA.  Small Regulatory RNA: miRNA Folded miRNAs are cleaved by special enzymes into smaller double-stranded fragments. One strand of the miRNA combines with RISC and base pairs with a region of the target mRNA. The mRNA bound to the miRNA/RISC cannot be translated. TRANSLATIONAL REGULATION: PROTEINS THAT BIND UTRs -impact mRNA stability Post-transcriptional regulation of gene expression Iron-Response Element Activity  Translational Regulation The most common mechanism of translational regulation affects the initiation process – mRNA sequence recognized by binding protein can block ribosome Gene Regulation Example: Iron Metabolism Iron is essential: humans use ~20 mg/day to make new red blood cells. Too much free iron is toxic. Iron can be safely transported to cells in the bloodstream when bound to a protein called transferrin. Transferrin-bound iron is taken into the cells by binding to a cell surface protein called the transferrin receptor. Cells can safely store iron by binding it to a protein called ferritin. Elements of Iron Response Elements of Iron Response