B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 76
Текст из файла (страница 76)
These two histone marks constitute a unique histonemodification pattern that occurs in subsets of nucleosomes in human cells.Here the two histone tails are indicated by green dotted lines, and only halfof one nucleosome is shown. (Adapted from A.J. Ruthenburg et al., Cell145:692–706, 2011. With permission from Elsevier.)H3 tail exitfrom coreH4 tail exitfrom coreChapter 4: DNA, Chromosomes, and Genomes200Figure 4–38 Schematic diagram showinghow a particular combination of histonemodifications can be recognized by areader complex.
A large protein complexthat contains a series of protein modules,each of which recognizes a specific histonemark, is schematically illustrated (green).This “reader complex” will bind tightly onlyto a region of chromatin that containsseveral of the different histone marks thatit recognizes. Therefore, only a specificcombination of marks will cause thecomplex to bind to chromatin and attractthe additional protein complexes (purple)needed to catalyze a biological function.protein modulesscaffoldbinding to specificproteinhistone modificationson nucleosomereadercomplexcovalentmodificationon histone tail(mark)READER PROTEINBINDS ANDATTRACTS OTHERCOMPONENTSprotein complex withcatalytic activities andadditional binding sitesattachment to other components in nucleus,leading to gene expression, gene silencing,or other biological functionsee Figure 7–20).
But after a modifying enzyme “writes” its mark on one or a fewneighboring nucleosomes, events that resemble a chain reaction can ensue. Insuch a case, the “writer enzyme” works in concert with a “reader protein” locatedin the same protein complex. The reader protein contains a module that recognizes the mark and binds tightly to the newly modified nucleosome (see Figure(A)AMM MPAAAAMMMBoC6M m4.43/4.36M M PMR KKSKRKKRK SK29 101417 182326 27 28364(B)modification statehistoneH3“meaning”trimethylMheterochromatin formation,gene silencingKtrimethylM9AKK49gene expressiontrimethylMK27gene silencing(Polycomb repressive complex)Figure 4–39 Some specific meaningsof histone modifications.
(A) Themodifications on the histone H3 N-terminaltail are shown, repeated from Figure4–34. (B) The H3 tail can be marked bydifferent sets of modifications that act incombination to convey a specific meaning.Only a small number of the meaningsare known, including the three examplesshown. Not illustrated is the fact that, asjust implied (see Figure 4–38), reading ahistone mark generally involves the jointrecognition of marks at other sites on thenucleosome along with the indicated H3tail recognition. In addition, specific levelsof methylation (mono-, di-, or trimethylgroups) are generally required. Thus,for example, the trimethylation of lysine9 attracts the heterochromatin-specificprotein HP1, which induces a spreadingwave of further lysine 9 trimethylationfollowed by further HP1 binding, accordingto the general scheme that will beillustrated shortly (see Figure 4–40).
Alsoimportant in this process, however, is asynergistic trimethylation of the histone H4N-terminal tail on lysine 20.CHROMATIN STRUCTURE AND FUNCTION201regulatory proteinhistone-modifyingenzyme (”writer protein”)reader proteinhistone modification (mark)NEW “READER–WRITER”COMPLEX BINDSREPEATSSPREADING WAVE OF CHROMATIN CONDENSATION4–36), activating an attached writer enzyme and positioning it near an adjacentnucleosome.
Through many such read–write cycles, the reader protein can carrythe writer enzyme along the DNA—spreading the mark in a hand-over-hand manner along the chromosome (Figure 4–40).In reality, the process is more complicated than the scheme just described.Both readers and writers are part of a protein complex that is likely to containMBoC6multiple readers and writers, andto m4.447/4.38require multiple marks on the nucleosome tospread. Moreover, many of these reader–writer complexes also contain an ATP-dependent chromatin remodeling protein (see Figure 4–26C), and the reader, writer,and remodeling proteins can work in concert to either decondense or condenselong stretches of chromatin as the reader moves progressively along the nucleosome-packaged DNA.A similar process is used to remove histone modifications from specific regionsof the DNA; in this case, an “eraser enzyme,” such as a histone demethylase or histone deacetylase, is recruited to the complex.
As for the writer complex in Figure4–40, sequence-specific DNA-binding proteins (transcription regulators) directwhere such modifications occur (discussed in Chapter 7).Some idea of the complexity of the above processes can be derived from theresults of genetic screens for genes that either enhance or suppress the spreadingand stability of heterochromatin, as manifest in effects on position effect variegation in Drosophila (see Figure 4–32). As pointed out previously, more than 100such genes are known, and most of them are likely to code for subunits in one ormore reader–writer–remodeling protein complexes.Figure 4–40 How the recruitmentof a reader–writer complex canspread chromatin changes along achromosome.
The writer is an enzymethat creates a specific modification on oneor more of the four nucleosomal histones.After its recruitment to a specific site on achromosome by a transcription regulatoryprotein, the writer collaborates with areader protein to spread its mark fromnucleosome to nucleosome by means ofthe indicated reader–writer complex.
Forthis mechanism to work, the reader mustrecognize the same histone modificationmark that the writer produces; its bindingto that mark can be shown to activatethe writer. In this schematic example, aspreading wave of chromatin condensationis thereby induced. Not shown are theadditional proteins involved, including anATP-dependent chromatin remodelingcomplex required to reposition the modifiednucleosomes.202Chapter 4: DNA, Chromosomes, and GenomesBarrier DNA Sequences Block the Spread of Reader–WriterComplexes and thereby Separate Neighboring ChromatinDomainsThe above mechanism for spreading chromatin structures raises a potential problem. Inasmuch as each chromosome contains one continuous, very long DNAmolecule, what prevents a cacophony of confusing cross-talk between adjacentchromatin domains of different structure and function? Early studies of positioneffect variegation had suggested an answer: certain DNA sequences mark theboundaries of chromatin domains and separate one such domain from another(see Figure 4–31).
Several such barrier sequences have now been identified andcharacterized through the use of genetic engineering techniques that allow specific DNA segments to be deleted from, or inserted in, chromosomes.For example, in cells that are destined to give rise to red blood cells, a sequencecalled HS4 normally separates the active chromatin domain that contains thehuman β-globin locus from an adjacent region of silenced, condensed chromatin.If this sequence is deleted, the β-globin locus is invaded by condensed chromatin.This chromatin silences the genes it covers, and it spreads to a different extent indifferent cells, causing position effect variegation similar to that observed in Drosophila.
As described in Chapter 7, the consequences are dire: the globin genesare poorly expressed, and individuals who carry such a deletion have a severeform of anemia.In genetic engineering experiments, the HS4 sequence is often added to bothends of a gene that is to be inserted into a mammalian genome, in order to protectthat gene from the silencing caused by spreading heterochromatin.
Analysis ofthis barrier sequence reveals that it contains a cluster of binding sites for histoneacetylase enzymes. Since the acetylation of a lysine side chain is incompatiblewith the methylation of the same side chain, and specific lysine methylations arerequired to spread heterochromatin, histone acetylases are logical candidates forthe formation of DNA barriers to spreading (Figure 4–41). However, several othertypes of chromatin modifications are known that can also protect genes fromsilencing.(A)spreadingheterochromatinnuclear poreeuchromatinbarrier protein(B)barrier protein(C)barrier proteinFigure 4–41 Some mechanisms ofbarrier action.
These models are derivedfrom experimental analyses of barrieraction, and a combination of several ofthem may function at any one site.(A) The tethering of a region of chromatin toa large fixed site, such as the nuclear porecomplex illustrated here, can form a barrierthat stops the spread of heterochromatin.(B) The tight binding of barrier proteins toa group of nucleosomes can make thischromatin resistant to heterochromatinspreading.
(C) By recruiting a group ofhighly active histone-modifying enzymes,barriers can erase the histone marks thatare required for heterochromatin to spread.For example, a potent acetylation of lysine9 on histone H3 will compete with lysine 9methylation, thereby preventing the bindingof the HP1 protein needed to form a majorform of heterochromatin.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
