页数：57页文件大小：1.09 MB来源： 分子生物学基因Geneppt课件
本课件为《分子生物学》第21章转录调控（Regulation of Transcription），依据 Gene VII 教材编排，沿CpG islands等小节推进，讲解本章核心概念与分子机制，配逐页图示与文字版。
Chapter 21 Regulation of Transcription
Activation of gene structure Initiation of transcription Processing the transcript Transport to cytoplasm Translation of mRNA
Table 21.1 Incucible transcription factors bind to response elements that identify groups of promoters or enhancers subject to coordinate control.21.2 Response elements identify genes under common regulation Regulatory Agent Module Consensus Factor Heat shockHSECNNGAANNTCCNNGHSTFGlucocorticoidGRETGGTACAAATGTTCTRecept or Phorbol esterTRETGACTCAAP1 SerumSRECCATATTAGGSRF.
说明：原页为数据表，源文抽取后列标题与数值粘连，无法安全切分为表格，此处保留原文文字，建议对照原课件图片补充表格内容。
Figure 21.1 The regulatory region of a human metallothione in gene contains regulator elements in both its promoter and enhancer. The promoter has elements for metal induction; an enhancer has an element for response to glucocorticoid. Promoter elements are shown above the map, and proteins that bind them are indicated below.
Figure 21.2 The activity of a regulatory transcription factor may be controlled by synthesis of protein, covalent modification of protein, ligand binding, or binding of inhibitors that sequester the protein or affect its ability to bind to DNA.
Figure 28.19 Oncogenes that code for transcription factors have mutations that inactivate transcription (v-erbA and possibly v-rel) or that activate transcription (v-jun and v-fos).
Figure 21.3 Transcription factor SP1 has a series of three zinc fingers, each with a characteristic pattern of cysteine and histidine residues that constitute the zinc-binding site.
Figure 21.4 Zinc fingers may form a-helices that insert into the major groove, associated with b-sheets on the other side.
Figure 21.5 The first finger of a steroid receptor controls specificity of DNA-binding (positions shown in red); the second finger controls specificity of dimerization (positions shown in blue). The expanded view of the first finger shows that discrim in at ion between GRE and ERE target sequences rests on two amino acids at the base.
Receptor is a transmembrane protein, located in the plasma membrane, that binds a ligand in a domain on the extracellular side, and as a result has a change in activity of the cytoplasmic domain. (The same term is sometimes used also for the steroid receptors, which are transcription factors that are activated by binding ligands that are steroids or other small molecules.)
Figure 21.6 Several types of hydrophobic small molecules activate transcription factors. Corticoids and steroid sex hormones are synthesized from cholesterol, vitamin D is a steroid, thyroid hormones are synthesized from tyrosine, and retinoic acid is synthesized from isoprene (in fish liver).
Figure 21.7 Glucocorticoids regulate gene transcription by causing their receptor to bind to an enhancer whose action is needed for promoter function.
Figure 21.8 Receptors for many steroid and thyroid hormones have a similar organization, with an individual N-terminal region, conserved DNA-binding region, and a C-terminal hormone-binding region.
Figure 21.8 Receptors for many steroid and thyroid hormones have a similar organization, with an individual N-terminal region, conserved DNA-binding region, and a C-terminal hormone-binding region.
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Figure 21.5 The first finger of a steroid receptor controls specificity of DNA-binding (positions shown in red); the second finger controls specificity of dimerization (positions shown in blue). The expanded view of the first finger shows that discrim in at ion between GRE and ERE target sequences rests on two amino acids at the base.
Figure 21.19 Coactivators may have HAT activities that acetylate the tails of nucleosomal histones.
Figure 21.20 A repressor complex contains three components: a DNA binding subunit, a corepressor, and a histone deacetylase.
Figure 21.9 TR and RAR bind the SMRT corepressor in the absence of ligand. The promoter is not expressed. When SMRT is displaced by binding of ligand, the receptor binds a coactivator complex. This leads to activation of transcription by the basal apparatus.
Figure 21.10 The homeodomain may be the sole DNA-binding motif in a transcriptional regulator or may be combined with other motifs. It represents a discrete (60 residue) part of the protein.
Figure 21.11 The homeodomain of the Antennapedi a gene represents the major group of genes containing homeoboxes in Drosophila; engrailed(en) represents another type of homeotic gene; and the mammalian factor Oct-2 represents a distantly related group of transcription factors. The homeodomain is conventionally num be red from 1 to 60. It starts with the N-terminal arm, and the three helical regions occupy residues 10-22,28-38, and 42-58.
Figure 21.12 Helix 3 of the homeodomain binds in the major groove of DNA, with helices 1 and 2 lying out side the double helix. Helix 3 contacts both the phosphate backbone and specific bases. The N-terminal arm lies in the minor groove, and makes additional contacts.
Figure 29.8 The posterior pathway has two branches, responsible for abdominal development and germ cell formation.
Figure 21.13 All HLH proteins have regions corresponding to helix 1 and helix 2, separated by a loop of 10-24 residues. Basic HLH proteins have a region with conserved positive charges immediately adjacent to helix 1.
Figure 21.14 An HLH dimer in which both subunits are of the bHLH type can bind DNA, but a dimer in which one subunit lacks the basic region cannot bind DNA.
Figure 21.15 The basic regions of the bZIP motif are held together by the dimerization at the adjacent zipper region when the hydrophobic faces of two leucine zippers interact in parallel orientation.
Figure 20.19 An enhancer contains several structural motifs. The histogram plots the effect of all mutations that reduce enhancer function to <75% of wild type. Binding sites for proteins are indicated below the histogram.
Chromatin remodeling describes the energy-dependent displacement or reorganiz at ion of nucleosomes that occurs in conjuncti on with activation of genes for transcription.
Figure 21.16 The pre-emptive model for transcription of chromatin proposes that if nucleosomes form at a promoter, transcription factors (and RNA polymerase) cannot bind. If transcription factors (and RNA polymerase) bind to the promoter to establish a stable complex for initiation, histones are excluded.
Figure 21.17 The dynamic model for transcription of chromatin relies upon factors that can use energy provided by hydrolysis of ATP to displace nucleosomes from specific DNA sequences.
Figure 21.18 Hormone receptor and NF1 cannot bind simultaneously to the MMTV promoter in the form of linear DNA, but can bind when the DNA is presented on a nucleosomal surface.
Figure 21.18 Hormone receptor and NF1 cannot bind simultaneously to the MMTV promoter in the form of linear DNA, but can bind when the DNA is presented on a nucleosomal surface.
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HAT(histone acetyl transferase) enzymes modify histones by addition of acetyl groups; some transcriptional coactivators have HAT activity.
HDAC(histone deacetyltransferase) enzymes remove acetyl groups from histones; they may be associated with repressors of transcription.
Figure 20.26 An upstream transcription factor may bind a coactivator that contacts the basal apparatus.
Figure 21.19 Coactivators may have HAT activities that acetylate the tails of nucleosomal histones.
Figure 21.20 A repressor complex contains three components: a DNA binding subunit, a corepressor, and a histone deacetylase.
Figure 21.21 Pc-G proteins do not initiate repression, but are responsible for maintaining it.
Figure 19.45 Extension of heterochromatin inactivates genes. The probability that a gene will be inactivated depends on its distance from the heterochromatin region.
Domain of a chromosome may refer either to a discrete structural entity defined as a region within which supercoiling is independent of other domains; or to an extensive region including an expressed gene that has heightened sensitivity to degradation by the enzyme DNAase I.
MAR(matrix attachment site; also known as SAR for scaffold attachment site) is a region of DNA that attaches to the nuclear matrix.
Figure 4.1 Each of the a-like and b-like globin gene families is organized into a single cluster that includes functional genes and pseudogenes (y).
Figure 4.1 Each of the a-like and b-like globin gene families is organized into a single cluster that includes functional genes and pseudogenes (y).
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Figure 21.22 A globin domain is marked by hypersensitive sites at either end. The group of sites at the 5′side constitutes the LCR and is essential for the function of all genes in the cluster.
Figure 19.42 Sensitivity to DNAase I can be measured by determining the rate of disappearance of the material hybridizing with a particular probe.
Figure 21.23 Specialized chromatin structures that include hypersensitive sites mark the ends of a domain in the D. melanogaster genome and insulate genes between them from the effects of surrounding sequences.
Figure 21.24 A protein that binds to the insulator scs′is localized at interbands in Drosophila polytene chromosomes. Red staining identifies the DNA (the bands) on both the upper and lower samples; green staining identifies BEAF32 (often at interbands) on the upper sample. Yellow shows coincidence of the two labels. Some of the more prominent stained interbands are marked by white lines. Photograph kindly provided by Uli Laemmli.
Figure 21.25 The insulator of the gypsy transposon blocks the action of an enhancer when it is placed between the enhancer and the promoter.
Figure 29.32 The homeotic genes of the ANT-C complex confer identity on the most anterior segments of the fly. The genes vary in size, and are interspersed with other genes. The antpgene is very large and has alternative forms of expression.
Figure 21.26 Fab-7is a boundary element that is necessary for the independence of regulatory elements iab-6 and iab-7.
Figure 21.27 Domains may possess three types of sites: insulators to prevent effects from spreading between domains; MARs to attach the domain to the nuclear matrix; and LCRs that are required for initiation of transcription.
Figure 21.28 The restriction enzyme MspI cleaves all CCGG sequences whether or not they are methylated at the second C, but HpaII cleaves only nonmethylated CCGG tetramers.
Figure 21.29 The results of MspI and HpaII cleavage are comp a red by gel electrophoresis of the fragments.
Figure 13.30 Replication of methylated DNA gives hemimethylated DNA, which maintains its state at GATC sites until the Dam methylase restores the fully methylated condition.
Figure 21.30 The typical density of CpG doublets in mammalian DNA is ~1/100 bp, as seen for a g-glob in gene. In a CpG-rich island, the density is increased to >10 doublets/100 bp. The island in the APRT gene starts ~100 bp upstream of the promoter and extends ~400 bp into the gene. Each vertical line represents a CpG doublet.
Figure 21.20 A repressor complex contains three components: a DNA binding subunit, a corepressor, and a histone deacetylase.
1.Some regulatory promoter elements are present in many genes and are recognized by ubiquitous factors; others are present in a few genes and are recognized by tissue-specific factors. 2.Several groups of transcription factors have been identified by sequence homologies. 3.Another motif involved in DNA-binding is the zinc finger, which is found in proteins that bind DNA or RNA (or sometimes both). 4.Steroid receptors were the first members identified of a group of transcription factors in which the protein is activated by binding a small hydrophobic hormone.5.The leucine zipper contains a stretch of amino acids rich in leucine that are involved in dimerization of transcription factors.
Summary
6.HLH (helix-loop-helix) proteins have amphipathic helices that are responsible for dimerization, adjacent to basic regions that bind to DNA.7.Many transcription factors function as dimers, and it is common for there to be multiple members of a family that form homodimers and heterodimers. 8.The existence of a pre initiation complex signals that the gene is in an "active" state, ready to be transcribed.9.The variety of situ at ions in which hypersensitive sites occur suggests that their existence reflects a general principle. 10.Genes whose control regions are organized in nucleosomes usually are not expressed.
Summary
11.Acetyl at ion of histones occurs at both replication and transcription and could be necessary to form a less compact chromatin structure. 12.Active chromatin and inactive chromatin are not in equilibrium. 13.A group of hypersensitive sites upstream of the cluster of -globin genes forms a locus control region (LCR) that is required for expression of all of the genes in the domain. 14.CpG islands contain concentr at ions of CpG doublets and often surround the promoters of constitutively expressed genes, although they are also found at the promoters of regulated genes. 15.The formation of heterochromatin occurs by proteins that bind to specific chromosomal regions (such as telomeres) and that interact with histones.
Summary
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