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1、Regulation of Gene Expression于 敏 代谢与分子医学教育部重点实验室 1. Gene Expression and the Regulation of Gene ExpressionGene Expression Biological processes, such as transcription, and in case of proteins, also translation, that yield a gene product. A gene is expressed when its biological product is present and a
2、ctive. Gene expression is regulated at multiple levels.Type of gene expressionConstitutive expressionSome genes are essential and necessary for life, and therefore are continuously expressed, such as those enzymes involved in TAC. These genes are called housekeeping genes. Induction and repression T
3、he expression levels of some genes fluctuate in response to the external signals. Regulation of Gene Expression Prokaryotic organisms regulate gene expression in response to their environment. Eukaryotic cells regulate gene expression to maintain homeostasis in the organism.Gene expression must be r
4、egulated in several different dimensions10 wks14 wks1 day6 mos12 mos18 mosAt different stages of the life cycle, different genes need to be on and off.In time:In space:Paddock S.W. (2001). BioTechniques 30: 756 - 761.Each colored stripe in this fly embryo shows the expression of a different gene or
5、set of genes. The spatial regulation of these genes allows the embryo to be divided up into different regions that will give rise to the head, the internal organs, the abdomen, etc.and in abundance:Clyde et al. (2003). Nature 426:849-853Note how the gene whose expression is indicated in blue varies
6、in abundance from strong expression (bold arrow) to weak (thin arrow) within its expression domain. These differences in strength of gene expression have important functional consequences.RNA polymeraseDNAmRNATranscriptional controlTranslational controlPost-translational controlProteinRibosomeRNA po
7、lymeraseOnset of transcriptionLife span (stability) of mRNATranslation rateProtein activation or inhibition (by chemical modification)Multi-level Regulation of gene expressionTranscriptional regulation is based on the interaction of specific DNA sequence and special proteinsTranscription initiation
8、is a key point of controlling gene expression. Basic elements that regulate the transcription include Special DNA sequences: Cis-acting elements Regulatory proteins : Trans-acting factor DNA-protein interaction and protein-protein interaction RNA polymerase Cis-acting elements is the special DNA seq
9、uence that can affect the expression of its own gene. Features of Cis-acting elementsTrans-acting factorsRegulatory Proteins Gene expression is often controlled by regulatory proteins binding to specific DNA sequences. regulatory proteins gain access to the bases of DNA at the major groove regulator
10、y proteins possess DNA-binding motifs DNA binding domain DBD- DNA结合结构域 Transcription activating domain- 转录活化结构域Domains of trans-acting factorsDNA-binding motifsDNA-binding motifs are regions of regulatory proteins which bind to DNA helix-turn-helix motif zinc finger motif leucine zipper motif helix-
11、loop-helix motifHelix-turn-helix motifsStructure: about 20 amino acids long 2 short alpha helicies ( 7 9 amino acids long) DNA recognition helix (binds specific DNA sequence) Recognition helix and 2nd helix form 90 angle very short turn ( NOT a beta-turn) Often glycine at start of the turn (helix br
12、eaker)17Homeodomain proteinsThe homeodomain ( 同源异形域) is a class of helix-turn- helix DNA-binding domain and recognizes DNA in essentially the same way as those bacterial proteins.Zinc-Finger MotifsCCH HZnCCH HZnCCH HZnSeveral subtypes (Cys4, Cys2-His2 ) Example: Cys2 His2 type Zinc does not interact
13、 with DNA Usually multiple zinc-fingers in a row At least some also bind RNA Consensus sequence: Y,F-X-C-X2-4-C-XXX-F-XXXXX-L-XX-H-X3-5-HBasic domainsLeucine zippers (bZip): Basic region of the protein binds to DNA Mainly act as dimers or other sometimes as other multimers Special alpha-helices allo
14、w formation of coiled-coil structures. Hydrophobic residues (Leu) align on one side of the helix, NOT Bind to DNA Example: AP-1(Jun and Fos),C/EBPThe activating regions are grouped on the basis of amino acids content. Acidic domains: contain both critical acidic amino acids and hydrophobic aa. yeast
15、 Gal4yeast Gal4 Glutamine-rich domainsma mmalian activator SP1 Proline-rich domains: mammalian activator CTF1Transcription Activation DomainsCharacteristics of Gene Expression of Prokaryotes Prokaryotic genes are polycistron （多顺反子）systems, that is, several relevant genes are organized together to fo
16、rm a transcription unit - operon （操纵子）. Prokaryotic cells often respond to their environment by changes in gene expression. Genes involved in the same metabolic pathway are organized in operons. Some operons are induced when the metabolic pathway is needed. Some operons are repressed when the metabolic pathway is no longer needed.2. Regulation of Prokaryotic Gene Exp
