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These plates in turncapture a group of microtubules from the mitotic spindle in order to partitionthe chromosomes accuratelv as described in Chaoter 17.ChromatinStructuresCanBeDirectlyInheritedTo explain the above observations, it has been proposed that de nouo centromere formation requires an initial seeding event, involving the formation of aspecialized DNA-protein structure that contains nucleosomes formed with theCENP-A variant of histone H3. In humans, this seeding event happens morereadily on arrays of alpha satellite DNA than on other DNA sequences.TheH3-H4 tetramers from each nucleosome on the parental DNA helix are directlyinherited by the daughter DNA helices at a replication fork (see Figure 5-3g).Therefore, once a set of GENP-A-containing nucleosomes has been assembledon a stretch of DNA, it is easy to understand how a new centromere could begenerated in the same place on both daughter chromosomes following eachround of cell division (Figure 4-5f ).The plasticity of centromeres may provide an important evolutionary advantage.
we have seen that chromosomes evolve in part by breakage and rejoiningevents (seeFigure 4-18). Many of these events produce chromosomes with twocentromeres, or chromosome fragments with no centromeres at all. Althoughrare, both the inactivation of centromeres and their ability to be activate d cJenouo231STRUCTUREOFCHROMATINTHEREGULATIONr'":"".::::-iH::"_.1r n n e ra n oouter kinetochoreplateschromatin containing centromeresoecifichistone H3 variantc h r o m a t i nc o n t a i n i n gn o r m a lh i s t o n eH 3 t h a t i sdimethylated at lysine4m i c r o t u b u l e sIchromatin containingcentromere-sPecifich i s t o n eH 3 v a r i a n tpericentricheterochromatin/c o h e s i nm o l e c u l e sl i n k i n gs i s t e rchromatidsmicrotubulesk in e t o c h o r e(c)c h r o m a t i nc o n t a i n i n gc e n t r o m e r e - s p eicci fh i s t o n eH 3 v a r i a n t(B)c h r o m a t i nc o n t a i n i n gn o r m a lh i s t o n eH 3 t h a t i sdimethylated at lysine4may occasionally allow newly formed chromosomes to be maintained stably,thereby facilitating the process of chromosome evolution.There are some striking similarities between the formation and maintenance of centromeres and the formation and maintenance of other regions ofheterochromatin.
In particulal the entire centromere forms as an all-or-noneentity, suggestinga highly cooperative addition of proteins after a seedingevent'Moreover, once formed, the structure seemsto be directly inherited on the DNAas part of each round of chromosome replication.to EucaryoticAdd UniqueFeaturesChromatinStructuresFunctionChromosomeAlthough a great deal remains to be learned about the functions of differentchromatin structures, the packaging of DNA into nucleosomes was probablycrucial for the evolution of eucaryotes like ourselves' Complex multicellularorganisms would appear to be possible only if the cells in different lineages canspLcializeby changing the acceisibility and responsivenessof many hundreds ofglrr.r to genetic r"udort. As described in Chapter 22, each cell has a storedir"1no.y ol itr purt developmental history in the regulatory circuits that controlits many genes.Althoirgh bacteria also require cell memory mechanisms, the complexity ofthe memory circuits required by higher eucaryotesis unprecedented' The packaging of seiected regions of eucaryotic genomes into different forms of chroriatiir md es possibie a type of cell memory mechanism that is not available tobacteria.
The irucial featuie of this uniquely eucaryotic form of gene regulationis the storage of the memory of the state of a gene on a gene-by-genebasis-inthe form oi local chromatin structures that can persist for various lengths oftime. At one extreme are structures Iike centric heterochromatin that, onceestablished,are stably inherited from one cell generation to the next (seeFigureFigure4-50 The organizationandfunction of the chromatin that forms(A)By staininghuman centromeres.stretchedchromatinfiberswiththe alphalabeledantibodies,fluorescentlysatelliteDNAthat formscentricin humansis seento beheterochromatinpackagedinto alternatingblocksofchromatin.One blockis formedfrom acontainingthelong stringof nucleosomesH3 varianthistone(green);theCENP-Athat areother blockcontainsnucleosomesmarkedwith a dimethyllysine4specially(red).Eachblock is more than a thousandlong.(B)A modelfor thenucleosomesorganizationof the two types of centricAs in Yeast,theheterochromatin.that containthe H3 variantnucleosomeshistoneform the kinetochore.(C)Theof the centricand pericentricarrangementon a humanmetaphaseheterochromatinasdeterminedbYchromosome,usingthe samemicroscopyfluorescenceantibodiesas in (A).(AdaptedfromB.A.Sullivanand G.H.Karpen,Nat.Struct.2004'WithMoL Biol.11:1076-1083,Ltd.)from MacmillanPublishersoermission232Chapter4: DNA,Chromosomes,and Genomes(A)S6H 2 A - H 2 Bd i m e r*-: Gsr e p l i c a t i o nf o r kh i s t o n e sa d d e dt onew nucleosomesH 3 - H 4t e t r a m e rp a r e n t a lc h r o m a t i nnewly assembledchromatin withn o r m a lH 3 h i s t o n e(B)H 2 A - H 2 Bd i m e rC E N P - AH 3H4icentromere-specificn u c l e o s o m edsi r e c tt h e a d d i t i o no fnew histonesH4newlyassembledchromatinwithcentromere-specificH3histoneFigure4-51 A modelfor the direct inheritanceof centromericheterochromatin.(A)The normalassemblyof chromatinon the two daughterDNAhelicesproducedat a replicationfork requiresthe depositionofH2A-H2Bdimersonto directlyinheritedH3-H4tetramers,aswell asthe assemblyof new histoneoctamers(seeFigure5-38 for details).(B)At a centromere,the inheritanceof H3 variant_H4tetramersseedstheformationof new histoneoctamersthat likewisecontainthe variantH3 histone.A similarseedingprocesscouldcausethe adjacentblocksof centricheterochromatin(containingH3 modifiedat dimethyllysine4;seeFigure4-50)to be inherited.Althoughthe detailsarenot known,the seedingprocessis likelytoinvolveothercentromericproteinsthat areinheritedalongwith the nucleosomeslseeFigure+-!Z;.4-51).
Closely related mechanisms that are likewise based on the direct inheritance of parental forms of chromatin by the daughter DNA helices behind thereplication fork are thought to be responsible for other types of condensedchromatin (Figure 4-sz). For example, ihe permanently silenied, classicaltweheterochromatinproteins nucleosomesheterochromatin euchromatrnII cHROMOSOMEI DUPLICATION.4.t\n1n11\z r,/ U \./\,/N E WH E T E R O C H R O M A T I NP R O T E I NASD D E DT OP R O P E R LMYO D I F I E DHISTONESheterochromatin euchromarrnFigure4-52 How the packagingof DNAin chromatincan be inheritedduringchromosomereplication.In this model,someof the specializedchromatincomponentsaredistributedto eachdaughterchromosomeafterDNAduplication,alongwith the speciallymarkednucleosomesthat they bind.AfterDNAreplication,the inheritednucleosomesthat arespeciallymodified,actingin concertwith the inheritedchromatincomponents,changethepatternof histonemodificationon thenewlyformeddaughternucteosomesnearby.Thiscreatesnew bindingsitesforthe samechromatincomponents,whichthen assembleto completethe structure.The latter processis likelyto involvecodereader-writer-remodelingcomplexesoperatingin a mannersimilarto thatpreviouslyillustratedin Figure4-46.THEGLOBAL5TRUCTUREOFCHROMOSOMES,Iof heterochromatin contains the HPI protein, whereas the condensed chromatin that coats important developmental regulatory genes is maintained bythe polycomb group of proteins.
The latter type of heterochromatin silences alarge number of genesthat encode gene regulatory proteins early in embryonicdevelopment, covering a total of about 2 percent of the human genome, and itis removed only when each individual gene is needed by the developing organism (discussed in Chapter 22). Although other tlpes of inherited chromatinstructures exist, it is not yet clear how many different t)?es there are: the number could certainly exceed l0 (seep.
238). The fundamental importance of thismechanism for distinguishing different genes is schematically represented in(Figure 4-53).other forms of chromatin can have a shorter lifetime, much less than thedivision time of the cell; however, many have a built-in persistence that helps tospecificchromatinstructureson genesfeedback loopsm a i n t a i n i n gc h r o m a t i nstructuresmediate biological function.Su m m a r yDespite the uniform assemblyof chromosomal DNA into nucleosomes,a large uarietyof dffirent chromatin structuresare possiblein eucaryotic organisms.
This uariety isbased on a large setof reuersiblecoualent modifications of the four histones in thenucleosomecore. Thesemodifications include the mono-, di-, and tri-methylation ofmany dffirent lysinesidechains,an important reactionthat is incompatiblewith theacetylation of the same lysines.Specifi,ccombinations of the modifications mark eachnucleosomewith a histone code.The histone code is read when protein modules thatare part of a larger protein complex bind to the modified nucleosomesin a region ofchromatin.
Thesecode-readerproteins then attract additional proteins that catalyzebiologically releuantfunctio ns.Some code-readerprotein complexescontain a histone-modtfying enzyme,suchAas a histone methylase,that "writes" the same mark that the code-readerrecognizes.reader-writer-remodelingcomplex of this type cqn spreada specfficform of chromatinhetefor long distancesalong a chromosome.In particular, large regionsof condensediscommonlyrochromatin are thought to be formed in this way. Heterochromatinotherfound around centromeresand near telomeres,but it is also present &t manyusuallyheterochromatinpackagingDNAintoofpositionsin chromosomes.The tightsilencesthe geneswithin it.The phenomenon of position effect uariegation prouides good euidencefor thedirect inheritance of condensedforms of chromatin by the daughter DNA helicesformed at a replication fork, and a similar mechanism appears to be responsibleformaintaining the specializedchromatin at centromeres.More generally,the ability totransmit specificchromatin structuresfrom one cell generationto the next prouidesthe basisfor an epigeneticcell memory processthat is likely to be critical for maintaining the complex set of dffirent cell stetesrequired by complex multicellularorganBms.OFCHROMOSOMESSTRUCTURETHEGLOBALHaving discussed the DNA and protein molecules from which the 30-nm chromatin fiber is made, we now turn to the organization of the chromosome on amore global scale.As a 30-nm fiber, the typical human chromosome would stillbe 0.1 cm in length and able to span the nucleus more than 100 times.
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