英文医学培训课件：Regulation of gene expression in eukaryotes 2015 Clinical 8

1、Regulation of Gene Expression in Eukaryotes,马端 MD, PhD, Professor,Sickness,Malnutrition,Inherited Diseases,Acquired Diseases,Diseases Interacted by Gene and Environment,Chromosome Diseases Multiple Gene Diseases Single Gene Diseases Mitochondrial Diseases Epigenetic Diseases,Trauma Suffocate Radiati

2、on Starvation,Classification of Diseases,Eukaryote Has a Very Huge Genome,Transcription and Translation are Separated in Eukaryote,RNA polymerase I：28S, 18S and 5.8S rRNAs RNA polymerase II: mRNAs, most snRNA and microRNAs RNA polymerase III: tRNAs, rRNA 5S and other small RNAs,RNA Poly II Transcrip

3、tion Initiation Machinery,Type II Promotor,Initiator: 5Y-C-A+1-N-T/A-Y-Y-Y-3. Y: C/T, N: any base. TATA box (TATAAAA ) is at -25 and is involved in positioning the enzyme for correct initiation. CAAT box (CCAATCT) is at 75 and is recognized by a large group of transcription factors and plays a stron

4、g role in determining the efficiency of the promoter. GC box is at -90 contains the sequence GGGCGG and is recognized by the factor SP1.,UBF1: increases the ability of SL1 to bind to the core promoter. SL1: 1 TBP, 3 TAF1, positions RNA polymerase I at the start point.,RNA Polymerase I,Transcription

5、Units for RNA Polymerase III,Type 1: 5S rRNA Type 2: tRNA Type 3: snRNA,Transcription Factor and Cis Elements,hTERT - Human Telomerase Reverse Transcriptase,CpG Island,CpG island is a region with at least 200 bp, and a GC percentage that is greater than 50%, and with an observed-to-expected CpG rati

6、o that is greater than 60%. About 70% of human promoters have a high CpG content. 56 million CpG sites,What Is DNA Methylation ?,DNA methylation is the covalent addition of a methyl group (CH3) to cytosine within the context of CpG dinucleotide .,Biochemical Pathways for DNA Methylation,DNA Methyltr

7、ansferases,Dnmt3b, of which expression is stage- and cell type-specific, can methylate nucleosome core region, and may contribute to global methylation. Chromatin remodeling that promotes the creation of naked DNA may regulate Dnmt3a-dependent methylation. Dnmt3L, which has no DNA methylation activi

8、ty, is shown to be indispensable for the global methylation in germ cells. Dnmt3L directly interacts with Dnmt3a and Dnmt3b to facilitate their activity.,What Are the Results of DNA Methylation?,DNA methylation can cause gene silencing by interference with recognition and binding of positively actin

9、g transcription factors Promotion of interaction and recruitment of negative factors.,DNA Methylation And Diseases,DNA Methyltransferase Inhibitors,Tet：Ten-eleven translocation methylcytosinedioxygenase,DNA Demethylation,Chromatin Activation,Chromatin is the combination of DNA and proteins that make

10、s up chromosomes. Euchromatin has a loose structure, whereas heterochromatin is more tightly condensed. Genes are actively transcribed in euchromatin but are repressed in heterochromatin.,DNase I Hypersensitive SitesWithin Chromatin,Histones are subject to post translational modification by enzymes

11、primarily on their N-terminal tails, but also in their globular domains. Such modifications include methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, and ADP-ribosylation. This affects their function of gene regulation.,Histone Modification,List of Human Histone Proteins,Functi

12、ons in Transcription,Histone Code,How Might Histone Modifications Alter Transcriptional Activity?,Lead directly to changes in chromatin structure that influence the accessibility of the chromatin to the transcriptional machinery Serve as recognition elements for factors that alter chromatin structur

13、e,mRNA Processing,Capping,Alternative RNA Splicing,RNA Editing,Polyadenylation,mRNA Degradation,Nonsense-Mediated mRNA Decay,Stability Regulation of IRE-BP on the Transferrin Receptor mRNA,Low Fe,Transferrin Receptor mRNA,5,Coding Region,Active IRE-BP,3,Poly(A)n,Translation,TfR Protein,IRE,Transferr

14、in Receptor mRNA,IRE-BP: Iron-response element-binding protein,RNA Interference, siRNA,Functional Pathways of Small Regulatory RNAs,antisense RNAs (asRNAs),Transcription initiation RNAs (tiRNAs),Long non-coding RNA (lncRNA),More than 1000 lncRNA-disease entries 475 lncRNA interaction entries, includ

15、ing 321 lncRNAs and 221 diseases The predicted associated diseases of 1564 human lncRNAs.,/lncrnadisease,Translation Control,Phosphorylation of eIF2 Regulates Synthesis of Protein,Translation Regulation of IRE-BP on Ferritin mRNA,Low Fe,Poly (A)n,Poly (A)n,Leaky Scanning,Questions,Whats the difference of regulation of gene