B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 78
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After DNAreplication, the inherited nucleosomes thatare specially modified, acting in concertwith the inherited chromatin components,change the pattern of histone modificationon the newly formed nucleosomes nearby.This creates new binding sites for thesame chromatin components, which thenassemble to complete the structure. Thelatter process is likely to involve reader–writer–remodeling complexes operating in amanner similar to that previously illustratedin Figure 4–40.nucleosomeshistonemodificationheterochromatineuchromatinCHROMOSOMEDUPLICATIONNEW HETEROCHROMATINPROTEINS ADDED TO REGIONWITH MODIFIED HISTONESheterochromatineuchromatinheterochromatineuchromatinheterochromatin. In particular, the entire centromere forms as an all-or-noneentity, suggesting that the creation of centromeric chromatin is a highly cooperative process, spreading out from an initial seed in a manner reminiscent ofthe phenomenon of position effect variegation that we discussed earlier.
In bothcases, a particular chromatin structure, once formed, seems to be directly inherited on the DNA following each round of chromosome replication. A cooperativerecruitment of proteins, along with the action of reader–writer complexes, canthus not only account for the spreadingof specific forms of chromatin in spaceMBoC6 m4.52/4.44along the chromosome, but also for its propagation across cell generations—fromparent cell to daughter cell (Figure 4–44).Experiments with Frog Embryos Suggest that both Activating andRepressive Chromatin Structures Can Be Inherited EpigeneticallyEpigenetic inheritance plays a central part in the creation of multicellular organisms.
Their differentiated cell types become established during development, andpersist thereafter even through repeated cell-division cycles. The daughters of aliver cell persist as liver cells, those of an epidermal cell as epidermal cells, and soon, even though they all contain the same genome; and this is because distinctivepatterns of gene expression are passed on faithfully from parent cell to daughtercell. Chromatin structure has a role in this epigenetic transmission of informationfrom one cell generation to the next.One type of evidence comes from studies in which the nucleus of a cell froma frog or tadpole is transplanted into a frog egg whose own nucleus has beenremoved (an enucleated egg).
In a classic set of experiments performed in 1968,it was shown that a nucleus taken from a differentiated donor cell can be reprogrammed in this way to support development of a whole new tadpole (see Figure7–2). But this reprogramming occurs only with difficulty, and it becomes less andless efficient as nuclei from older animals are used. Thus, for example, less than2% of the enucleated eggs injected with a nucleus from a tadpole epithelial celldeveloped to the swimming tadpole stage, compared with 35% when the donornuclei were taken instead from an early (gastrula-stage) embryo.
With new experimental tools, the cause of this resistance to reprogramming can now be traced.It arises, at least in part, because specific chromatin structures in the original differentiated nucleus tend to persist and be transmitted through the many cell-division cycles required for embryonic development. In experiments with Xenopusembryos, specific forms of either repressive or active chromatin structures couldbe demonstrated to persist through as many as 24 cell divisions, causing the misplaced expression of genes. Figure 4–45 briefly describes one such experiment,206Chapter 4: DNA, Chromosomes, and Genomessomite cells expressing MyoDenucleated eggdonor Xenopusembryonuclear transfertwo-cell stage embryoinject normalH3.3 mRNAno injection(control)inject mutantH3.3 mRNAblastulastageembryoscells analyzed for MyoD expression and for H3.3 histone on MyoD promoterHIGH MyoDEPIGENETICMEMORY(much MyoDproteinproduced)MODERATE MyoDEPIGENETICMEMORYLOW MyoDEPIGENETICMEMORY(little MyoDproteinproduced)focused on chromatin containing the histone variant, H3.3.
We shall return tothese phenomena in the final section of Chapter 22, where we discuss stem cellsn4.105/4.45and the ways in which one cellMBoC6type canbe converted into another.Chromatin Structures Are Important for Eukaryotic ChromosomeFunctionAlthough a great deal remains to be learned about the functions of different chromatin structures, the packaging of DNA into nucleosomes was probably crucialfor the evolution of eukaryotes like ourselves. To form a complex multicellularorganism, the cells in different lineages must specialize by changing the accessibility and activity of many hundreds of genes.
As described in Chapter 21, thisprocess depends on cell memory: each cell holds a record of its past developmental history in the regulatory circuits that control its many genes. That record, itseems, is partly stored in the structure of the chromatin.Although bacteria also have cell memory mechanisms, the complexity of thememory circuits in higher eukaryotes is unparalleled. Strategies based on localvariations in chromatin structure, unique to eukaryotes, can enable individualgenes, once they are switched on or switched off, to stay in that state until somenew factor acts to reverse it. At one extreme are structures like centromeric chromatin that, once established, are stably inherited from one cell generation to thenext. Likewise, the major “classical” type of heterochromatin, which contains longarrays of the HP1 protein (see Figure 4–39), can persist stably throughout life.
Incontrast, a form of condensed chromatin that is created by the Polycomb group ofproteins serves to silence genes that must be kept inactive in some conditions, butare active in others. The latter mechanism governs the expression of a large number of genes that encode transcription regulators important in early embryonicdevelopment, as discussed in Chapter 21. There are many other variant forms ofchromatin, some with much shorter lifetimes, often less than the division time ofthe cell. We shall say more about the variety of chromatin types in the next section.Figure 4–45 Evidence for the inheritanceof a gene-activating chromatin state.The well-characterized MyoD geneencodes a master transcription regulatoryprotein for muscle, MyoD (see p.
399). Thisgene is normally turned on in the indicatedregion of the young embryo where somitesform. When a nucleus from this region isinjected into an enucleated egg as shown,many of the progeny cell nuclei abnormallyexpress the MyoD protein in non-muscleregions of the “nuclear transplant embryo”that forms. This abnormal expression canbe attributed to maintenance of the MyoDpromoter region in its active chromatinstate through the many cycles of celldivision that produce the blastula-stageembryo—a so-called “epigenetic memory”that persists in this case in the absenceof transcription.
The active chromatinsurrounding the MyoD promoter containsthe variant histone H3.3 (see Figure 4–35)in a Lys4 methylated form. As indicated,an overproduction of this histone causedby injecting excess mRNA encoding thenormal H3.3 protein increases both H3.3occupancy on the MyoD promoter andthe epigenetic MyoD production, whereasinjection of an mRNA producing a mutantform of H3.3 that cannot be methylatedat Lys4 reduces the epigenetic MyoDproduction.
Such experiments provideevidence that an inherited chromatin stateunderlies the epigenetic memory observed.(Adapted from R.K. Ng and J.B. Gurdon,Nat. Cell Biol. 10:102–109, 2008. Withpermission from Macmillan Publishers Ltd.)THE GLOBAL STRUCTURE OF CHROMOSOMES207SummaryIn the chromosomes of eukaryotes, DNA is uniformly assembled into nucleosomes,but a variety of different chromatin structures is possible. This variety is based on alarge set of reversible covalent modifications of the four histones in the nucleosomecore. These modifications include the mono-, di-, and trimethylation of many different lysine side chains, an important reaction that is incompatible with the acetylation that can occur on the same lysines. Specific combinations of the modificationsmark many nucleosomes, governing their interactions with other proteins.
Thesemarks are read when protein modules that are part of a larger protein complexbind to the modified nucleosomes in a region of chromatin. These reader proteinsthen attract additional proteins that perform various functions.Some reader protein complexes contain a histone-modifying enzyme, such as ahistone lysine methylase, that “writes” the same mark that the reader recognizes.
Areader–writer–remodeling complex of this type can spread a specific form of chromatin along a chromosome. In particular, large regions of condensed heterochromatin are thought to be formed in this way. Heterochromatin is commonly foundaround centromeres and near telomeres, but it is also present at many other positions in chromosomes. The tight packaging of DNA into heterochromatin usuallysilences the genes within it.The phenomenon of position effect variegation provides strong evidence for theinheritance of condensed states of chromatin from one cell generation to the next.
Asimilar mechanism appears to be responsible for maintaining the specialized chromatin at centromeres. More generally, the ability to propagate specific chromatinstructures across cell generations makes possible an epigenetic cell memory processthat plays a role in maintaining the set of different cell states required by complexmulticellular organisms.THE GLOBAL STRUCTURE OF CHROMOSOMESHaving discussed the DNA and protein molecules from which the chromatin fiberis made, we now turn to the organization of the chromosome on a more globalscale and the way in which its various domains are arranged in space.
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