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Transcriptional-level control (10) • Researchers use the following techniques to find DNA sequences involved in regulation: – Deletion mapping – DNA footprinting – Genome-wide location analysis • Allows simultaneous monitoring of all the sites within the genome that carry a particular activity. Use of chromatin immunoprecipitation to identify transcription factor-binding sites Transcriptional-level control (11) • The Glucocorticoid Receptor: An Example of Transcriptional Activation – PEPCK is a key enzyme controlled by a variety of transcription factors called response elements. Transcriptional-level control (12) • The Glucocorticoid Receptor (continued) – The glucocorticoid receptor (GR) is a nuclear receptor that includes a ligand-binding domain and a DNA-binding transcription factor. – The GR binds to a glucocorticoid response element (GRE), which is a palindrome. Activation of a gene by a steroid hormone Transcriptional-level control (13) • Transcriptional Activation: The Role of Enhancers, Promoters, and Coactivators – Enhancers are DNA elements that stimulate transcription. • Can be located very far upstream from the regulated gene. • A promoter and its enhancers can be “cordoned off” from other elements by sequences called insulators. A survey of transcriptional activation Transcriptional-level control (14) • Coactivators serve as intermediates for transcription factors, and are divided into two classes: – Those that interact with the transcription machinery. – Those that alter chromatin structure modifying histones to regulate transcription. • By using histone acetyltransferases (HATS) • By using chromatin remodeling complexes Selective localization of histone modifications A model of events following the binding of a transcriptional activator Several alternative actions of chromatin remodeling The nucleosomal landscape of yeast genes Transcriptional-level control (15) • Transcriptional Activation from Poised Polymerases – RNA polymerases are also bound to “transcriptionally silent” genes that initiate transcription but do not transition to elongation. – These polymerases are ready for transcription but are poised by inhibitory factors. – Gene transcription at the level of elongation may be important in activation of genes. Transcriptional-level control (16) • Transcriptional Repression – Histone deacetylases (HDACs) remove acetyl groups and repress transcription. • HDACs are subunits of larger complexes acting as corepressor. • Corepressors are recruited to specific gene loci by transcription factors that cause the targeted gene to be silenced. A model for transcriptional repression Transcriptional-level control (17) • Transcriptional Repression (continued) – DNA Methylation • It is carried out by DNA methylatransferases. • It silences transcription in eukaryotic cells. • Methylation patterns of gene regulatory regions change during cellular differentiation. Transcriptional-level control (18) • Transcriptional Repression (continued) – DNA Methylation and Transcriptional Repression • Activity of certain genes varies according to changes in DNA methylation. • DNA methylation serves more to maintain a gene in an inactive state rather than to initially inactivate it. • DNA methylation is not an universal mechanism for inactivating eukaryotic genes. Changes in DNA methylation levels during mammalian development Transcriptional-level control (19) • Transcriptional Repression (continued) – Genomic Imprinting • Activity of certain genes, called imprinted genes, depends on whether they originated with the sperm or egg. • Active and inactive versions of imprinted genes differ in their methylation patterns. • Disturbances in imprinting patterns have been implicated in a number of rare human genetic disorders. 12.5 Processing-level Control (1) • Protein diversity can be generated by alternative splicing. • Alternative splicing can become complex, allowing different combinations of exons in the final mRNA product. Processing-level Control (2) • There are factors that can influence splice site selection. • Exonic splicing enhancers serve as binding sites for regulatory proteins. Processing-level Control (3) • RNA Editing – Specific nucleotides can be converted to other nucleotides through mRNA editing. – RNA editing ca create new splice sites, generate stop codons, or lead to amino acid substitutions. – It is important in the nervous system, where messages need to have A converted to I (inosine) to generate a glutamate receptor. 12.6 Translational-level Control (1) • Translation of mRNAs that have been transported from the nucleus to the cytoplasm is regulated. – Translational-level control occurs via interactions of specific mRNAs and proteins in the cytoplasm. – Regulatory proteins act on unstranslated regions (UTRs) at both their 5’ and 3’ ends. – UTRs contain nucleotide sequences used by the cell to mediate translational-level control. Translational-level Control (2) • Cytoplasmic Localization of mRNAs – In the fruit fly embryo the development of anterior-posterior axis is regulated by the localization of specific mRNAs along the axis in the egg. – Cytoplasmic localization of mRNAs is determined by their 3’ UTRs. Cytoplasmic localization of mRNAs Cytoplasmic localization of mRNAs Translational-level Control (3) • The Control of mRNA Translation – Several important processes depend on mRNAs that were synthesized at a previous time and stored in the cytoplasm in an inactive state. – Other mechanisms influence the rate of translation of specific mRNAs through proteins that recognize specific elements in the UTRs of those mRNAs. – Example: mRNA that codes for ferritin. A model for the mechanism of translational activation of mRNAs following fertilization Translational-level Control (4) • The Control of mRNA Stability – The lifetimes of eukaryotic mRNA vary widely. – Poly(A) tail length may influence the longevity of mRNA. • As an mRNA remains in the cytoplasm, its poly(A) tail tends to be reduced. • When the tail is about 30 A residues, the tail is shortened. – Certain destabilizing proteins in the 3’ UTR may affect the rate of poly(A) tail shortening. mRNA degradation in mammalian cells Translational-level Control (5) • The Control of mRNA Stability (continued) – Deadenylation, decapping, and 5’ 3’ degradation occur within small transient cytoplasmic granules (P-bodies). – P-bodies can also store mRNAs no longer being translated. Translational-level Control (6) • The Role of MicroRNAs in Translational-level Control – miRNAs act by binding to site in the 3’UTR of their target mRNAs. – Translational-level by miRNAS has been a bit controversial. – Some studies suggest that miRNAs carry out translational-level control by inducing the degradation of target mRNA. Potential mechanisms by which miRNAs might decrease gene expression at translational level 12.7 Post-translational Control: Determining Protein Stability (1) • The factors that control a protein’s lifetime are not well understood. • Protein stability may be determined by the amino acids on the N-terminus. • Degradation of proteins is carried out within hollow, cylindrical proteasomes. Post-translational Control: Determining Protein Stability (2) • Proteasomes recognize proteins linked to ubiquitin. • Ubquitin is transferred by ubiquitin ligases to proteins being degraded. • Once polubiquitanated, a protein is recognized by the cap of the proteasome. • Once degraded, the component amino acids are released back into the cytosol. Proteasome structure Proteasome structure