B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 74
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In a typical mammalian cell, morethan 10% of the genome is packaged in this way.The DNA in heterochromatin typically contains few genes, and when euchromatic regions are converted to a heterochromatic state, their genes are generallyswitched off as a result. However, we know now that the term heterochromatinencompasses several distinct modes of chromatin compaction that have differentimplications for gene expression. Thus, heterochromatin should not be thoughtof as simply encapsulating “dead” DNA, but rather as a descriptor for compactchromatin domains that share the common feature of being unusually resistantto gene expression.The Heterochromatic State Is Self-PropagatingThrough chromosome breakage and rejoining, whether brought about by a natural genetic accident or by experimental artifice, a piece of chromosome that isnormally euchromatic can be translocated into the neighborhood of heterochromatin.
Remarkably, this often causes silencing—inactivation—of the normallyactive genes. This phenomenon is referred to as a position effect. It reflects aspreading of the heterochromatic state into the originally euchromatic region,and it has provided important clues to the mechanisms that create and maintainheterochromatin. First recognized in Drosophila, position effects have now beenobserved in many eukaryotes, including yeasts, plants, and humans.CHROMATIN STRUCTURE AND FUNCTION1951 2 3 4 5barrierheterochromatineuchromatingenes1 2 3 4 51 2 3 4 5early in the developing embryo, heterochromatin forms and spreads into neighboringeuchromatin to different extents in different cells1 2 3 4 51 2 3 4 51 2 3 4 51 2 3 4 5CHROMOSOMETRANSLOCATIONcell proliferation1 2 3 4 5heterochromatineuchromatinclone of cells withgene 1 inactive(A)clone of cells withgenes 1, 2, and 3 inactiveclone of cells withno genes inactivated(B)Figure 4–31 The cause of position effect variegation in Drosophila.
(A) Heterochromatin (green) is normally prevented fromspreading into adjacent regions of euchromatin (red) by barrier DNA sequences, which we shall discuss shortly. In flies thatinherit certain chromosomal rearrangements, however, this barrier is no longer present. (B) During the early development of suchflies, heterochromatin can spread into neighboring chromosomal DNA, proceeding for different distances in different cells. Thisspreading soon stops, but the established pattern of heterochromatin is subsequently inherited, so that large clones of progenycells are produced that have the same neighboring genes condensed into heterochromatin and thereby inactivated (hence the“variegated” appearance of some of these flies; see Figure 4–32).
Although “spreading” is used to describe the formation ofnew heterochromatin close to previously existing heterochromatin, the term may not be wholly accurate. There is evidence thatduring expansion, the condensation of DNA into heterochromatin can “skip over” some regions of chromatin, sparing the genesthat lie within them from repressive effects.In chromosome breakage-and-rejoining events of the sort just described, thezone of silencing, where euchromatin is converted to a heterochromatic state,spreads for different distances in differentMBoC6early m4.36/4.29cells in the fly embryo. Remarkably, these differences then are perpetuated for the rest of the animal’s life: ineach cell, once the heterochromatic condition is established on a piece of chromatin, it tends to be stably inherited by all of that cell’s progeny (Figure 4–31).
Thisremarkable phenomenon, called position effect variegation, was first recognizedthrough a detailed genetic analysis of the mottled loss of red pigment in the fly eye(Figure 4–32). It shares features with the extensive spread of heterochromatin thatinactivates one of the two X chromosomes in female mammals. There too, a random process acts in each cell of the early embryo to dictate which X chromosomewill be inactivated, and that same X chromosome then remains inactive in all thecell’s progeny, creating a mosaic of different clones of cells in the adult body (seeFigure 7–50).These observations, taken together, point to a fundamental strategy of heterochromatin formation: heterochromatin begets more heterochromatin. Thispositive feedback can operate both in space, causing the heterochromatic state tospread along the chromosome, and in time, across cell generations, propagatingthe heterochromatic state of the parent cell to its daughters.
The challenge is toexplain the molecular mechanisms that underlie this remarkable behavior.White geneat normallocationbarrierheterochromatinrare chromosomeinversionbarrierWhite genenear heterochromatinFigure 4–32 The discovery of positioneffects on gene expression. The Whitegene in the fruit fly Drosophila controls eyepigment production and is named after themutation that first identified it. Wild-typeflies with a normal White gene (White+)have normal pigment production, whichgives them red eyes, but if the White geneis mutated and inactivated, the mutantflies (White–) make no pigment and havewhite eyes.
In flies in which a normal Whitegene has been moved near a region ofheterochromatin, the eyes are mottled,with both red and white patches. The whitepatches represent cell lineages in whichthe White gene has been silenced by theeffects of the heterochromatin. In contrast,the red patches represent cell lineages inwhich the White gene is expressed. Earlyin development, when the heterochromatinis first formed, it spreads into neighboringeuchromatin to different extents in differentembryonic cells (see Figure 4–31).
Thepresence of large patches of red and whitecells reveals that the state of transcriptionalactivity, as determined by the packaging ofthis gene into chromatin in those ancestorcells, is inherited by all daughter cells.Chapter 4: DNA, Chromosomes, and Genomes196(A) LYSINE ACETYLATION AND METHYLATION ARE COMPETING REACTIONSHONCCHCH2ONCCHCH2HONCCHCH2HONCCHCH2HONCCHCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2+NHHNH3COlysineNH3CH+NHH3CH+NH3CCH3+CH3CH3CH3acetyl lysinemonomethyl lysinedimethyl lysineFigure 4–33 Some prominent types of covalent amino acid side-chainmodifications found on nucleosomal histones.
(A) Three different levelsof lysine methylation are shown; each can be recognized by a differentbinding protein and thus each can have a different significance for the cell.Note that acetylation removes the plus charge on lysine, and that, mostimportantly, an acetylated lysine cannot be methylated, and vice versa.(B) Serine phosphorylation adds a negative charge to a histone. Modificationsof histones not shown here include the mono- or dimethylation of an arginine,the phosphorylation of a threonine, the addition of ADP-ribose to a glutamicacid, and the addition of a ubiquityl, sumoyl, or biotin group to a lysine.As a first step, one can carry out a search for the molecules that are involved.This has been done by means of genetic screens, in which large numbers ofmutants are generated, after which one picks out those that show an abnormality of the process in question.
Extensive genetic screens in Drosophila, fungi, andmice have identified more than 100 genes whose products either enhance or suppress the spread of heterochromatin and its stable inheritance—in other words,genes that serve as either enhancers or suppressors of position effect variegation.Many of these genes turn out to code for non-histone chromosomal proteins thatinteract with histones and are involved in modifying or maintaining chromatinstructure. We shall discuss how they work in the sections that follow.The Core Histones Are Covalently ModifiedMBoC6at ManyDifferent Sitesm4.38/4.31The amino acid side chains of the four histones in the nucleosome core are subjected to a remarkable variety of covalent modifications, including the acetylationof lysines, the mono-, di-, and trimethylation of lysines, and the phosphorylationof serines (Figure 4–33). A large number of these side-chain modifications occuron the eight relatively unstructured N-terminal “histone tails” that protrude fromthe nucleosome (Figure 4–34).
However, there are also more than 20 specific sidechain modifications on the nucleosome’s globular core.All of the above types of modifications are reversible, with one enzyme serving to create a particular type of modification, and another to remove it. Theseenzymes are highly specific. Thus, for example, acetyl groups are added to specificlysines by a set of different histone acetyl transferases (HATs) and removed by a setof histone deacetylase complexes (HDACs).
Likewise, methyl groups are added tolysine side chains by a set of different histone methyl transferases and removedby a set of histone demethylases. Each enzyme is recruited to specific sites onthe chromatin at defined times in each cell’s life history. For the most part, theinitial recruitment depends on transcription regulator proteins (sometimes called“transcription factors”). As we shall explain in Chapter 7, these proteins recognizeand bind to specific DNA sequences in the chromosomes. They are produced attrimethyl lysine(B) SERINE PHOSPHORYLATIONHONCCHCH2HONCCHCH2OHserineOOPO_OphosphoserineCHROMATIN STRUCTURE AND FUNCTION197H3PAAA ASGRGKQGGKARAKAKTRSSRAGLQFPVGRVH3side view159H2A13 15H4MPAAAAAPEPAKSAPAPKKGSKKAVTKAQKKDGKKRK512 14 1520H2B2324AMAAAAMM MM M PMM MPARTKQTARKSTGGKAPRKQLATKAARKSAPATGGVKH2BH2B2H2A49 101417182326 2728H336H2AH4H3AAP M AMMAASGRGKGGKGLGKGGAKRHRKVLRDNIQGITH3H2A13581216N-terminal tailsH2BH2BH4KEY:H2AM methylationH420P phosphorylationglobulardomainsA acetylationbottom view(A)(B)Figure 4–34 The covalent modification of core histone tails.
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