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Chapter 17 Regulation of Gene Expression in Eukaryotes Lecture Presentation by Dr. Cindy Malone, California State University Northridge © 2015 Pearson Education, Inc. Repaso de histonas y acetilación https://youtu.be/N53WZP_ILj4 © 2015 Pearson Education, Inc. Chapter Contents 17.1 Eukaryotic Gene Regulation Can Occur at Any of the Steps Leading from DNA to Protein Product 17.2 Eukaryotic Gene Expression Is Influenced by Chromatin Modifications 17.3 Eukaryotic Transcription Initiation Requires Specific Cis-Acting Sites Continued © 2015 Pearson Education, Inc. Chapter Contents 17.4 Eukaryotic Transcription Initiation Is Regulated by Transcription Factors That Bind to Cis-Acting Sites 17.5 Activators and Repressors Interact with General Transcription Factors and Affect Chromatin Structure 17.6 Gene Regulation in a Model Organism: Transcription of the GAL Genes of Yeast Continued © 2015 Pearson Education, Inc. Chapter Contents 17.7 Posttranscriptional Gene Regulation Occurs at All the Steps from RNA Processing to Protein Modification 17.8 RNA Silencing Controls Gene Expression in Several Ways 17.9 Programmed DNA Rearrangements Regulate Expression of a Small Number of Genes 17.10 ENCODE Data Are Transforming Our Concepts of Eukaryotic Gene Regulation © 2015 Pearson Education, Inc. 17.1 Eukaryotic Gene Regulation Can Occur at Any of the Steps Leading from DNA to Protein Product © 2015 Pearson Education, Inc. Section 17.1: Eukaryotic Gene Regulation Eukaryotic gene regulation is more complex than that in prokaryotes – Greater amount of DNA that is associated with histones and other proteins – mRNAs must be spliced, capped, and polyadenylated prior to transport from nucleus – Genes on numerous chromosomes are enclosed in a double membrane nucleus continued © 2015 Pearson Education, Inc. Section 17.1: Eukaryotic Gene Regulation continued mRNAs have wide range of half-lives (t1/2) Modulation of mRNA translation, protein processing, modification, and degradation (Figure 17-1) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-1 17.2 Eukaryotic Gene Expression Is Influenced by Chromatin Modifications © 2015 Pearson Education, Inc. Section 17.2: Gene Expression Influenced by Chromatin Modifications Two structural features of eukaryotes distinguish them from prokaryotes – Eukaryotic genes are situated on chromosomes that occupy a distinct location – Eukaryotic DNA is combined with histones and nonhistone proteins to form chromatin – Compact chromatin structure inhibits transcription, replication, and DNA repair © 2015 Pearson Education, Inc. Section 17.2: Transcription Factory Transcription factories – Feature within nucleus that may contribute to gene expression – Nuclear sites that contain most of the active RNA polymerase and transcription regulatory molecules – Dynamic structures that form rapidly and disassemble upon stimulation and repression of transcription © 2015 Pearson Education, Inc. Section 17.2: Nucleosomal Modifications Nucleosomes modified via change in composition – Important step in gene regulation; involves changes to either nucleosome or DNA – Histones contain normal histone H2A – Variant histones (H2A.Z) affect nucleosome mobility and positioning on DNA – Nucleosome position may repress or activate transcription via gene promoter © 2015 Pearson Education, Inc. Section 17.2: Histone Modification Histone modification – Covalent bonding of functional groups onto Nterminal tails of histone proteins Most common: acetyl, methyl, phosphate – Acetylation decreases positive charge, which reduces affinity of histone to DNA – Histone acetylation of nucleosome is catalyzed by histone acetyltransferase enzymes (HATs): associated with increased transcription (Figure 17-2) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-2 Section 17.2: Chromatin Remodeling Chromatin remodeling – Involves repositioning or removal of nucleosomes on DNA – Repositioned nucleosomes make chromosome regions accessible to Transcription regulatory proteins Transcription activators RNAP II (RNA polymerase II) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-2 Section 17.2: DNA Methylation DNA methylation – Associated with decreased gene expression – Methylation occurs most often on cytosine of CG doublets in DNA – Methylation can repress transcription by binding to transcription factors of DNA © 2015 Pearson Education, Inc. 17.3 Eukaryotic Transcription Initiation Requires Specific Cis-Acting Sites © 2015 Pearson Education, Inc. Section 17.3: Cis-Acting Sequences Cis-acting sequence – Located on same chromosome as gene that it regulates – Required for accurate regulated transcription of genes Promoters Enhancers Silencers © 2015 Pearson Education, Inc. Section 17.3: Promoter Structure Promoter structure – Made up of DNA sequence elements including: Initiator (Inr) TATA box TFIIB recognition element (BRE) Downstream promoter element (DPE) Motif ten element (MTE) (Figure 17-4) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-4 Section 17.4: Proximal-Promoter Elements Promoters contain proximal-promoter elements – Located upstream of TATA and BRE motifs – Enhance levels of basal transcription – Examples: CAAT and GC boxes (Figure 17-5) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-5 Section 17.3: Enhancers and Silencers Enhancers and silencers regulate transcription of eukaryotic genes – Cis-acting transcription regulatory elements Enhancers: Located on either side of gene, some distance from gene, or even within gene – Important in reaching maximum level of transcription Silencers: Repress the level of transcription initiation © 2015 Pearson Education, Inc. Section 17.4: Transcription Factors Transcription factors – Transcription regulatory proteins – Target cis-acting sites of genes regulating expression – Activators increase transcription initiation – Repressors decrease transcription initiation Multiple transcription factors bind to several different enhancers and promoter elements and fine-tune the level of transcription initiation © 2015 Pearson Education, Inc. Section 17.4: Functional Domains Transcription factors (proteins) – Have two functional domains (clusters of amino acids with a specific function): – DNA-binding domain Binds to specific DNA sequences in the cis-acting regulatory site – Trans-activating domain Activates or represses transcription by binding to other transcription factors or RNA polymerase © 2015 Pearson Education, Inc. Section 17.5: Formation of RNA Pol II Initiation Complex Formation of RNA Pol II initiation complex General transcription factors (proteins) – Required at promoter to initiate basal or enhanced levels of transcription – Assembly of proteins in specific order forms pre-initiation complex (PIC) – PIC provides platform for RNAP II to recognize transcription start sites © 2015 Pearson Education, Inc. Section 17.5: Core Promoter TFIID Core promoter TFIID – General transcription factor that assists RNA Pol II at core promoter TFIID – First step in forming PIC – binding of TFIID to TATA box via TATA binding protein (TBP) (Figure 17-7) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-7 Section 17.5: Coactivators and Enhanceosome Coactivators – Interact with proteins and enable activators to make contact with promoter-bound factors – Coactivators form complex “enhanceosome” Enhanceosome – Interacts with transcription complex (Figure 17-8) Repressor proteins at silencer elements decrease rate of PIC assembly and RNA Pol II release © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-8 Section 17.7: Posttranscriptional Regulation Posttranscriptional regulation plays an equal, if not more significant, role compared to transcriptional control (perhaps the major type of regulation in eukaryotes) Mechanisms of posttranscriptional gene regulation – Control of alternative splicing – mRNA stability – Translation – RNA silencing © 2015 Pearson Education, Inc. Section 17.7: Alternative Splicing Alternative splicing – Generates different forms of mRNA from identical pre-mRNA (increases number of proteins) – Expression of one gene gives rise to numerous proteins with similar and different functions – Increases number of proteins made from one gene (Figure 17-11 and Figure 17-12) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-11 Section 17.7: Three Pathways of Degradation Pathways of degradation 1) Enzymes shorten length of poly-A tail • Binding of poly-A binding protein to tail stabilizes mRNA 2) Decapping enzymes removes 7-methylguanine cap – mRNA now unstable 3) Endonuclease cleaves mRNA internally © 2015 Pearson Education, Inc. Section 17.7: p53 Protein and Ubiquitin Translational and posttranslational regulation p53 protein – p53 levels increase if cell suffers DNA damage or metabolic stress – p53 is a transcription factor that induces transcription of Mdm2 gene (ubiquitin ligase, blocks transcription) – Ubiquitin tags proteins for degradation by enzymes © 2015 Pearson Education, Inc. Section 17.8: RNA Interference RNA interference (RNAi) – Sequence specific posttranscriptional regulation – Short RNA molecules regulate gene expression in cytoplasm of plants, animals, and fungi; repress translation and trigger mRNA degradation Phenomena known as RNA-induced gene silencing © 2015 Pearson Education, Inc. Section 17.8: Molecular Mechanisms Molecular mechanisms of RNA-induced gene silencing siRNA and microRNAs – Short, double-stranded ribonucleotides – siRNAs: Arise in cell due to virus infection – produce double-stranded RNA, which is recognized and cleaved by Dicer – microRNAs: Noncoding RNAs that negatively regulate gene expression (Figure 17-14) © 2015 Pearson Education, Inc. © 2015 Pearson Education, Inc. Figure 17-14