© 2005 Nature Publishing Group

© 2005 Nature Publishing Group

R E S E A R C H H I G H L I G H T S

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162 | MARCH 2005 | VOLUME 6 www.nature.com/reviews/genetics

Transcriptional silencing has untilnow been explained by one of twomodels: the first claimed that RNApolymerase or activating factorsare prevented from accessing theirtargets owing to conformationalchanges in silenced chromatin; thesecond placed the transcriptionalblock further downstream, afterthe transcription pre-initiationcomplex has formed. Elegantwork by Chen and Widom now shows that neither is likely to be correct. Their resultssupport a third model, in whichtranscriptional silencing occursby preventing the formation ofstable pre-initiation complexes atsilenced promoters.

Driven by a lack of consensus onthe molecular mechanisms oftranscriptional silencing in yeast,Chen and Widom quantitativelytested the two prevailing models.First, by engineering the yeastchromosome 3 to containappropriate recognition sites, theauthors quantified the accessibilityof DNA targets to foreign reporterproteins, including the site-specificDNA-binding protein LexA,in vivo. They found no evidence of reduced binding to silenced locithat would indicate involvement ofsteric hindrance, so discountingthe first model.

According to the second model,RNA polymerase II, although

present at the promoters ofsilenced loci, should be absentfrom their 3′ ends. Chen andWidom used silenced URA3 toscrutinize RNA polymerase IIoccupancy; chromatinimmunoprecipitation revealedthat there was much less RNApolymerase II at either thepromoter or the 3′ end of thesilenced URA3 when comparedwith the euchromatic locus,indicating that transcription is blocked before polymerase isrecruited. These results werefurther confirmed when thetranscription factors TFIIB andTFIIE, both of which are recruitedto the pre-initiation complex, were

Transcriptional silencing: the third way

G E N E E X P R E S S I O N

LocusLink — is there lifeafter death?By the time you read this,NCBI’s LocusLink will be nomore. As of 1 March 2005, itwill have been replaced byNCBI’s Entrez Gene.

Born in 1999, LocusLinkhas served the geneticcommunity well. It wascreated to help manage andaccess increasing amountsof sequence data and webresources. The firstpublication1 to describe itrefers to it as a “webdirectory” that “provides asingle point-of-access to avariety of gene-specificinformation sources includingweb resources and RefSeq”.

Throughout its life,LocusLink was continuouslyupdated to inform us not onlyabout the sequence andfunction of an increasingnumber of species but alsoabout the correct genenomenclature. So why did ithave to go, and what of itsreplacement?

In fact, it might be better toview the recent events as themetamorphosis of LocusLinkrather than its demise, asEntrez Gene incorporates allof the LocusLink data and canbe thought of as its enhancedextension. It provides a unifiedlook and feel for gene-specificinformation and contains datafor many more species,including mitochondrial andplastid genome data for morethan a half of them.

Entrez Gene has someimportant additionalfunctionality — for example, itcan display information aboutsplice variants, intron/exonorganization and a wealth ofdata on protein–proteininteractions. The ‘search’function is much improved —for example, one or morespecies or taxonomic groupsof interest can be used torestrict the queries. Moreover,query parameters can besaved and results sent to youby means of the ‘My NCBI’function, as information isupdated. The king is dead,long live the king!

Magdalena Skipper

REFERENCE 1Maglott, D. R. et al.NCBI’s LocusLink and RefSeq.Nucleic Acids Res. 28, 126–128(2000)

A new insight into the pathwaysinvolved in obesity has come from a surprising source — studies ofextremely skinny mice.

Mice that lack a functional Lpin1gene develop a condition that isknown as lipodystrophy, which is characterized by a severe lack ofadipose tissue. The lipin protein thatis encoded by this gene is expressed inadipose tissue and skeletal muscle,and the lack of fatty tissue in lipin-deficient mice is caused by a failure ofadipocytes to differentiate. Jack Phanand Karen Reue had previously shownthat lipin deficiency prevents micefrom becoming obese, and that thisworks both for mice that are overfedand those that are genetically predis-posed to obesity. This led them towonder whether reversing the situa-tion by increasing lipin levels wouldhave the opposite effect and causemice to become obese.

To test this, they made trans-genic mice that overexpressed Lpin1either in adipose tissue or in skeletalmuscle. In both cases, increased Lpin1

expression predisposed the mice toobesity. However, whereas theskeletal-muscle transgenicsbecame obese even on a stan-dard diet, mice that overex-pressed Lpin1 in adiposetissue only put on excessweight when they werefed a high-fat diet, indi-cating an important envi-ronmental contribution,which is reminiscent ofhuman obesity.

The authors thenshowed that the causes ofexcessive weight gain associ-ated with increased lipin levelswere mediated by different path-ways in the two types of transgenicmouse. Animals that overexpressLpin1 in adipose tissue showedincreased activation of genes that areinvolved in the storage and produc-tion of fat. By contrast, the weight-gain mechanism of transgenics withoverexpressed Lpin1 in skeletal musclewas associated with defects in energyexpenditure, including an increased

efficiencyin the conver-sion of food to body massand a reduced ability to use storedbody fat as an energy source. Thiswas also reflected at the molecular

Low-fat clues to obesity

O B E S I T Y