silicate grains seem to be concentrated near � Pic (as expected, due to Poynting–Robert-son drag).

Crystalline silicate grains are also concen-trated near � Pic. This could be attributed tothe higher temperatures there, becauseamorphous silicate grains are annealed(converted to crystalline form) above about1,100 K (ref. 9). Alternatively, these grainscould have been shed by comets entering �Pic’s inner solar system10.Carbon monoxidemolecules, which are easily destroyed byultraviolet radiation from � Pic, have beendetected in the � Pic disk3 — strongly imply-ing that they are being replaced through thecontinuing evaporation of comets. In ourown Solar System, a high proportion (about30%) of the silicate grains shed from cometssuch as Hale–Bopp are crystalline11.

The presence of small amorphous grainsat the particular radii of 16 and 30 AU isintriguing; these radii match the locations ofthe dust bands previously inferred for the �Pic disk7.Okamoto et al.1 have found that thedust grains at these radii are amorphous sili-cates and are small enough to require con-stant replenishment. These data stronglysuggest the presence of belts of comets or planetesimals at these radii in the � Picdisk (Fig. 1). The improved resolution ofOkamoto and colleagues’ data, however, hasled them further, to the detection of anotherdust belt at a radius of 6.4 AU. As the authorsdiscuss, this arrangement of a belt of plan-etesimals or comets at 6.4 AU as well as 16 AU

suggests the gravitational influence of ashepherding planet at a radius of 12 AU.

As for the dominance of amorphous sili-cates in these belts, it could be that there areno crystalline silicates at these radii (unlikethe situation inferred from comets from ourown Solar System), or that silicates are trans-formed within the planetesimals from crys-talline to amorphous form. Future work canconfirm or deny these hypotheses. But it isclear that astromineralogical observationswill provide further, exciting insight into theformation of rocky planets in � Pic and othersolar systems. ■

Steve Desch is in the Department of Physics andAstronomy, Arizona State University, Tempe,Arizona 85287-1504, USA.e-mail: steve.desch@asu.edu1. Okamoto, Y. K. et al. Nature 431, 660–663 (2004).

2. Lecavelier des Etangs, A. et al. Nature 412, 706–708 (2001).

3. Artymowicz, P. Astrophys. J. 335, L79–L82 (1988).

4. Mukai, T. & Giese, R. H. Astron. Astrophys. 131, 355–363

(1984).

5. Zuckerman, B., Song, I., Bessell, M. S. & Webb, R. A.

Astrophys. J. 562, L87–L90 (2001).

6. Molster, F. J. & Waters, L. B. F. M. in Astromineralogy (Lecture

Notes in Physics no. 609) (ed. Henning, T. K.) 121–170

(Springer, Berlin, 2003).

7. Wahhaj, Z. et al. Astrophys. J. 584, L27–L31 (2003).

8. Weinberger, A. J., Becklin, E. E. & Zuckerman, B. Astrophys. J.

584, L33–L37 (2003).

9. Hallenbeck, S. L., Nuth, J. A. III & Nelson, R. N. Astrophys. J.

535, 247–255 (2000).

10.Li, A. & Greenberg, M. Astron. Astrophys. 331, 291–313 (1998).

11.Wooden, D. et al. Astrophys. J. 517, 1034–1058 (1999).

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Molecular biology

No exception to reversibilityYi Zhang

Histone proteins, which serve as scaffolds for packaging DNA, can bemodified in numerous ways. It’s been thought that one modification,methylation, is irreversible — but that view must now change.

Each of our cells contains about twometres or so of DNA, which must bepacked down very tightly to fit into

the cell nucleus. The compact form of DNAis known as chromatin, the basic unit ofwhich consists of DNA wrapped around anoctamer of histone proteins1. The histonesare not merely architectural proteins, how-ever: they also influence chromatin dynam-ics. One way in which they do so is throughtheir covalent modification with certainchemical groups or small proteins — acetylgroups, phosphate groups, ubiquitin pro-teins or methyl groups2. Enzymes that cata-lyse the addition or removal of the firstthree modifications have been identified.

But enzymes that remove methyl groupshave been more elusive, raising the questionof whether methylation is an exception tothe rule: the only histone modification thatis irreversible3. Two new papers, however —published in Science by Wang et al.4 and inCell by Cuthbert et al.5 — reverse that view.

The histone octamer consists of twocopies each of four ‘core’ histones: H2A,H2B,H3 and H4.Methylation occurs on cer-tain lysine and arginine amino acids withinH3 and H4, and is catalysed by distinct fami-lies of enzymes6; PRMT1 and CARM1, forinstance, are enzymes involved in argininemethylation. Lysine residues can be mono-,di- or tri-methylated, whereas arginine

Figure 1 Reversing methylation in histone proteins. a, Three theoretical mechanisms: top, enzymaticdemethylation, perhaps regulated by the HDM enzyme; centre, replacement of methylated histonesby unmethylated variants; bottom, clipping of histone ‘tails’, by enzymes unknown. K, lysine; R,arginine. b, Wang et al.4 and Cuthbert et al.5 have discovered another mechanism: they show thatmethylated and unmethylated arginine amino acids in two histone proteins can be converted tocitrulline. A possible cycle of events is shown. Methylation of arginines is accomplished by thePRMT1 or CARM1 enzymes, with SAM (S-adenosyl-L-methionine) as cofactor; AdoHcy (S-adenosyl-L-homocysteine) is released. Conversion to citrulline is achieved by PAD4/PADI4. It remains unknownwhat then happens to citrulline — whether it is converted back to arginine (by an aminotransferaseenzyme, perhaps), or whether histones containing citrulline are replaced by unmodified versions.

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residues can only be mono- or di-methylated.Histone methylation has been linked to

biological processes ranging from the regu-lation of gene transcription, to the inactiva-tion of one copy of the X chromosome infemales, to RNA-mediated gene silencing2,6,7.One way in which it works is by serving as adocking site for other proteins2. The natureof a specific methylation determines the pro-tein that it recruits,which in turn dictates thebiological outcome (see, for example, ref.6).

Unlike other histone modifications,methylation has generally been regarded asstable3 — a notion that comes from earlystudies showing that histone proteins andmethylated lysine or arginine residues with-in them have similar turnover rates8. Butalthough a non-reversible methyl markwould fit with a role for histone methylationin long-term gene silencing, it is not compat-ible with situations in which rapid reversal ofgene expression takes place. To solve thisparadox, mechanisms including enzyme-catalysed demethylation, replacement ofmethylated histones by unmodified his-tones, and clipping of methylated histone‘tails’ have been proposed3,9 (Fig. 1a) — butnone has yet been demonstrated experimen-tally. Now,however,Wang et al.4 and Cuthbertet al.5 have found that the human enzyme peptidylarginine deiminase 4 (PAD4/PADI4)can catalyse the conversion of methylatedarginines to citrulline, providing yet anothermechanism by which histone methylation levels could be controlled (Fig.1b).

How is it that two groups independentlyidentified the same enzyme and came to similar conclusions? Previous studies10 estab-lished that arginine residues in other pro-teins can be converted to citrulline byenzymes of the peptidylarginine deiminasefamily. Of this family, only PAD4/PADI4 is found in the nucleus; moreover, its expres-sion correlates with the appearance ofcitrulline in histones11. These facts made it a good candidate for a histone argininedemethylase.

So Wang et al. and Cuthbert et al. carriedout direct tests of PAD4/PADI4 in vitro.They found that it ‘deiminated’ numerousunmethylated arginines — converted themto citrulline — in histones H3 and H4. It alsodecreased the amount of arginine methyla-tion that is catalysed by PRMT1 and CARM1in both histones. Notably, at the same timethat the amount of this methylationdecreased, the quantities of citrulline in bothhistones increased. The detection of methyl-amine as a released product4 supports theidea that methylated arginine is a genuinesubstrate of this enzyme. So, PAD4/PADI4can catalyse both the deimination ofunmethylated arginine and the ‘demethyl-imination’ of methylated arginine in vitro.As Wang et al. find, it can also do so in granu-locyte cells.

What are the consequences of these

reactions? First, as Cuthbert et al. show, theconversion of histone arginines to citrullinesactually prevents histone methylation byCARM1. Second, Wang et al. find thatdemethylimination of methylated histonearginines reverses the effects associated withmethylation. So, PAD4/PADI4 presumablyantagonizes the functions of the methylatingenzymes CARM1 and PRMT1. For instance,previous studies have linked histone argi-nine methylation by these enzymes to tran-scriptional activation by nuclear hormonereceptors12–15 — so PAD4/PADI4 is likely torepress such transcription. Indeed, bothgroups link the recruitment of PAD4/PADI4to an oestrogen-responsive gene, pS2, withthe appearance of citrullinated histones andthe downregulation of this gene.

These papers4,5 provide convincing evi-dence that the methylation of arginineamino acids in histone proteins can bereversed enzymatically. But, as ever, the find-ings raise questions. For example, it seemsthat PAD4/PADI4 has a very loose substratespecificity in vitro. It works on both methy-lated and unmethylated arginines. And thearginine residues it deiminates are not limi-ted to the sites that are targeted by CARM1and PRMT1; indeed, arginine 8 in histoneH3, a site not known to be methylated byeither enzyme, is the preferred target4. Theremight be an interplay between the citrullina-tion of H3 arginine 8 and the methylation ofH3 lysine 9, but for now the significance ofthis citrullination remains unknown.

The second issue worth noting is that, invitro,PAD4/PADI4 cannot demethyliminateH4 or H3 peptides containing di-methylatedarginines4,5.This presents a puzzle.Althoughmass-spectrometry analysis14,15 identifiedmono-methyl groups as the major methylform on arginine 3 in histone H4, mostarginines 17 and 26 in histone H3 become di-methylated after incubation with CARM1 invitro16. How, then, can this methylation beremoved? Although an unidentified enzymemight be required, the available evidencesuggests that PAD4/PADI4 is responsible: forinstance, in granulocytes, activation of thisenzyme led to less methylation on H4 argi-nine 3 and H3 arginine 17, as analysed usingsite-specific antibodies that recognize di-methylated arginine4. The most likely solu-tion is that PAD4/PADI4 can work only onintact chromatin substrates. Alternatively, itmight need to work with a partner.

As well as revealing that arginine methy-lation can be reversed,the new papers4,5 showthat a new form of histone proteins — con-taining citrulline residues — exists in cells.This finding, too, raises questions. Howstable are citrullinated histones? Do theyhave any effects on chromatin structure? Canother proteins recognize and bind to them?And what is the fate of these histones? Withregard to the last question,the transient pres-ence of citrullines in the pS2 gene5 suggests

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638 NATURE | VOL 431 | 7 OCTOBER 2004 | www.nature.com/nature

100 YEARS AGOThe recent tube operations in London have brought to the surface specimens of the London Clay from different districts.Samples of this clay taken from suchdifferent points as Hyde Park Corner,Brompton Road, and Haverstock Hill havebeen tested in the physical laboratory of theSouth-western Polytechnic for the presenceof a radio-active gas by Mr. H. Cottam,and he has been unable to detect with hisapparatus any marked quantity of active gasfrom the clays. With the same apparatus hehas detected quite easily the radio-activegas from the water of a deep well… whichgoes below the clay to the greensand. Wehave come to the conclusion that the LondonClay forms a floor through which the radio-active gas does not penetrate; or it may besaid that the radio-active substance onlytravels when the water with which it isassociated can travel. This is an argument in support of Prof. J. J. Thomson’s view, thatthe radio-active gas, which he found in deepwell waters, arises from the splitting up of atrace of soluble radium salt which comes upwith the water.From Nature 6 October 1904.

50 YEARS AGOLittle more than a hundred years havepassed since hunters such as GordonCumming were at their work among the vast herds of big game in the southernquarter of Africa, and little more than fiftysince Selous was making a living by ivoryhunting somewhat farther to the north. Allthose countless thousands of animals havenow disappeared for ever… The opening-upand white settlement of East Africa did notcome until later, but although the sameprocess of decimation began, and manyparts of the country have been cleared ofgame, it is still possible to see great herds of wild animals that recall the accounts of conditions in South Africa given by theearly travellers. Nevertheless, the presenceof enormous herds of game animals is quiteincompatible with the economic exploitationof the country and the rapid expansion ofthe native population; the game must go,and there can be no hope of its survivaloutside the National Parks and gamereserves… As yet, however, there ispractically no information available on the biology of these mammals, informationthat is essential for successfully managingsuch parks and reserves.From Nature 9 October 1954.

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that their rapid removal must be possible.The availability of site-specific antibodiesagainst citrullinated histones will allow atleast some of these issues to be addressed.And one final question: is the methylation of lysine residues in histone proteins alsoreversible? ■

Yi Zhang is in the Department of Biochemistry andBiophysics, Lineberger Comprehensive CancerCenter, University of North Carolina at Chapel Hill,Chapel Hill, North Carolina 27599-7295, USA.e-mail: yi_zhang@med.unc.edu1. Kornberg, R. D. & Lorch, Y. Cell 98, 285–294 (1999).

2. Jenuwein, T. & Allis, C. D. Science 293, 1074–1080

(2001).

3. Bannister, A. J., Schneider, R. & Kouzarides, T. Cell 109,

801–806 (2002).

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population made a last stand in the BritishIsles before dying out 10,500 years ago, but the Siberian population persisted for another3,000 years.

What caused the extinction of so manylarge mammals 10,000 or so years ago?Human hunting3, changes in climate or veg-etation, or both4, are often proposed to becausal factors. But the “‘ragged’ nature” (touse Stuart and colleagues’ phrase) of theseLate Pleistocene extinctions, with isolatedpockets of populations surviving for longer,suggests that the extinctions have a complexecology, with no single mechanism respon-sible for the demise of every species in every location.

Theories for both the expansion and theextinction of Irish elk populations, forinstance, often focus on the animals’ hugeantlers, which weighed 40 kilograms andspanned 3.5 metres,making them 30% largerthan those of modern moose. It has been suggested5 that female Irish elk selected maleswith large antlers, as this might have signifiedan ability to find sufficient food to supportbuilding and shedding a rack each year.This ability would then be passed on to theirmale progeny.

But the large antlers, which contained asmuch as 8 kilograms of calcium and 4 kilo-grams of phosphate, would have posed alarge annual nutritional burden on bulls6.The antlers would also be physically unwieldyin dense forests7. So both physical and nutri-tional constraints probably restricted the

Palaeontology

Ecology of ice-age extinctionsJohn Pastor and Ron A. Moen

The last ice age saw the extinction of numerous large mammals — butperhaps not as many as was thought. The woolly mammoth survived to much more recent times, and so, it now seems, did the Irish elk.

Sabre-toothed tigers, mastodons,woolly mammoths — these and manyother spectacular large mammals are

generally thought to have become extinctabout 10,000 years ago, at the end of thePleistocene epoch, otherwise known as thelast ice age. But it’s becoming clear that someof these species clung on tantalizingly closeto the present day.Thomas Jefferson’s instruc-tion to Meriwether Lewis and William Clarkto search for live woolly mammoths in theAmerican West in 1804 was perhaps a littleoptimistic. But the species survived onWrangel Island in the northeastern SiberianArctic until some 4,000 years ago1, making itcontemporaneous with the Bronze Age XiaDynasty in China. On page 684 of this issue,Stuart et al.2 report that another charismaticice-age mammal that was thought to havebecome extinct 10,000 years ago — the giantdeer or Irish elk (Megaloceros giganteus) —survived in western Siberia to the dawn ofhistoric times. The finding lends weight tothe idea that there is no one explanation forthe so-called Pleistocene extinctions.

The Irish elk (Fig. 1) must have cut animpressive figure, standing more than twometres high at the shoulder — about the sameas a bull moose, the largest living member ofthe deer family. But when and why did itbecome extinct? In their investigation, Stuartet al.2 began by carrying out radiocarbon dating of five skeletal specimens, including acomplete skeleton of an antler-bearing male.By combining this information with maps ofthe specimens’ locations, they show that Irishelk were widespread in Europe — from Ire-land to Russia, and from Scandinavia to theMediterranean — before 20,000 years ago.

NATURE | VOL 431 | 7 OCTOBER 2004 | www.nature.com/nature 639

But by the last glacial maximum 15,000 yearsago, they may have been restricted to refugesin the shrub steppes of central Asia. Fromthere, Irish elk apparently recolonized north-western Europe following the retreat of theAlpine and Scandinavian ice sheets during aperiod of climatic warming. The European

Figure 1 Prehistoric giant — artist’s impression of the Irish elk.

NA

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ON

4. Wang, Y. et al. Science doi:10.1126/science.1101400

(2004).

5. Cuthbert, G. L. et al. Cell 118, 545–553 (2004).

6. Zhang, Y. & Reinberg, D. Genes Dev. 15, 2343–2360

(2001).

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8. Byvoet, P. Arch. Biochem. Biophys. 152, 887–888 (1972).

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320–326 (2004).

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Pruijn, G. J. BioEssays 25, 1106–1118 (2003).

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49562–49568 (2002).

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Kouzarides, T. EMBO Rep. 3, 39–44 (2002).

13.Chen, D. et al. Science 284, 2174–2177 (1999).

14.Strahl, B. D. et al. Curr. Biol. 11, 996–1000 (2001).

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16.Schurter, B. T. et al. Biochemistry 40, 5747–5756

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intrinsic mortality (and a longer intrinsiclifespan) when all else is equal, many organ-isms face a trade-off between higher levels ofreproduction or lower levels of intrinsicmortality. One of the main reasons thatsenescence occurs is because repair is costly:resources that are devoted to maintaining anorganism are not available for reproduction.In the 1950s, Peter Medawar2 and GeorgeWilliams3 pointed out that high extrinsicmortality could favour shorter intrinsic life-span. Why, they reasoned, should an organ-ism invest in costly repair that will probablyonly ensure that it is in prime physical condi-tion when its life ends? Higher extrinsic mor-tality should favour low investment in repair,and thus a high intrinsic mortality and ashort intrinsic lifespan.

But this reasoning didn’t take account oftwo further factors.One is that higher extrin-sic mortality also slows the rate of popula-tion growth,and more slowly growing popu-lations are expected to evolve to have lowerrates of intrinsic mortality and a longer life-span4,5. The other is the interaction betweenextrinsic mortality factors and physiologicalrepair or maintenance5,6. If predators can beevaded by fast, but not by slow prey, greaterpredation risk should select for greatermaintenance of the body systems essentialfor fast movement.This higher level of repairwould then prolong intrinsic lifespan.

Higher extrinsic mortality (more preda-tors) could also have indirect effects thatMedawar and Williams did not consider. Forexample, it reduces population size, which in turn increases the abundance of food orother resources. These changes may havetheir own effects on both population growthand the level of intrinsic mortality favouredby selection. Other complications arise if themortality factor has a greater effect on someages than on others5,6 — if, for example,predators prefer to capture larger, older prey.As a result of these complicating features,many types of mortality are expected toreduce intrinsic death rates at some ageswhile increasing them at others6. In anyevent, theory suggests that higher extrinsicmortality will produce evolutionary condi-tions that can either extend or shorten theintrinsic lifespan.

Given these complexities, the curious feature of previous observational7 and experi-mental work8 has been its support for theMedawar–Williams prediction. There havebeen exceptions9, if only suggestively so. Butthe almost unanimous evidence that highextrinsic mortality is associated with shorterlifespan is puzzling because there is no reasonto believe that the conditions that producethe opposite outcome are rare in nature.

So it is reassuring that Reznick et al.1

found longer intrinsic lifespans in guppiesfrom populations characterized by higherpredation rates. The authors also looked atwhether these evolutionary changes might

be an indirect consequence of predator-caused deaths, such as the availability, in nat-ural settings, of more food for the remainingguppies. Reznick and colleagues’ study isunique in examining this effect. They foundthat food alone could not account for the difference in intrinsic mortalities seen intheir experiments, but that having morefood enhanced the lifespan-lengtheningeffect of a high-predation background.

There is no doubt that the guppies fromhigh-predation sites have both longer intrin-sic lifespans and longer reproductive spans.But is it valid to conclude that they have slower senescence? This is a more difficultquestion.A hypothetical population with nosenescence (that is, no age-related decline insurvival or reproduction) could still have ashort lifespan if it had a high mortality ratethat was independent of age. If guppies fromhigh-predation sites begin their adult lifewith a lower rate of intrinsic mortality thanthose from low-predation environments,they could have the same rate of increasewith age in their mortality rate, but wouldstill have a longer lifespan. One could thenargue that the two populations had identicalrates of senescence. Some measures of therate of change of intrinsic mortality with agesuggest that senescence is delayed in guppiesfrom high-predation sites.

However, senescence encompasses rela-tionships between many different compo-nents of fitness and age,none of which can beadequately summarized by a single number:there are many potential measures of the rateof senescence,and conclusions about this ratedepend on the measure chosen. It might bepossible to make a case that guppies fromhigh-predation environments are morerobust, but age at a rate equal to or higherthan that of low-predation guppies. Regard-less of the mathematical measure used toquantify the rate of senescence, the work of Reznick et al. clearly shows that rates of

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senescence differ among the different compo-nents of fitness examined:survival,reproduc-tion or swimming performance. The reasonsfor these differences are not yet understood.

It would be surprising if guppies were theonly species for which an added risk of mor-tality lengthens intrinsic lifespan. Similarstudies on other species will help us under-stand the underlying reasons why Medawarand Williams’ predictions hold for somespecies and not for others. Such studiesshould follow Reznick and colleagues’ lead in quantifying declines in several fitnesscomponents and studying the indirect eco-logical consequences of higher extrinsicmortality. ■

Peter A. Abrams is in the Department of Zoology,University of Toronto, 25 Harbord Street, Toronto,Ontario M5S 3G5, Canada.e-mail: abrams@zoo.utoronto.ca1. Reznick, D. N., Bryant, M. J., Roff, D., Ghalambor, C. K. &

Ghalambor, D. E. Nature 431, 1095–1099 (2004).

2. Medawar, P. B. An Unsolved Problem in Biology

(Lewis, London, 1952).

3. Williams, G. C. Evolution 11, 398–411 (1957).

4. Charlesworth, B. A. Evolution in Age-Structured Populations

(Cambridge Univ. Press, 1980).

5. Abrams, P. A. Evolution 47, 877–887 (1993).

6. Williams, P. D. & Day, T. Evolution 57, 1478–1488 (2002).

7. Ricklefs, R. E. Am. Nat. 152, 24–44 (1998).

8. Stearns, S. C., Ackermann, M., Doebeli, M. & Kaiser, M.

Proc. Natl Acad. Sci. USA 97, 3309–3313 (2000).

9. Miller, R. A., Harper, J. M., Dysko, R. C., Durkee, S. J.

& Austad, S. N. Exp. Biol. Med. 227, 500–508 (2002).

Figure 1 Star survivor — the longest lived of the guppies studied by Reznick et al.1. The photo wastaken shortly before her death at the age of 1,464 days.

CorrectionIn Yi Zhang’s News and Views article “Molecularbiology: No exception to reversibility” (Nature 431,637–639; 2004), there were errors in Fig. 1b. In the side chain of citrulline, a double bondshould have been shown between NH and O,rather than between NH and NH2. Several of the connecting atoms are erroneously shown as H rather than N. And the leaving methylamineshould have been represented as +NH3CH3 ratherthan +NH2CH3.

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