Low-Fat Clues to Obesity More

RESEARCH HIGHLIGHTS WEB WATCH OBESITY LocusLink — is there life after death? By the time you read this, NCBI’s LocusLink will be no Low-fat clues to obesity more. As of 1 March 2005, it will have been replaced by NCBI’s Entrez Gene. A new insight into the pathways expression predisposed the mice to Born in 1999, LocusLink involved in obesity has come from obesity. However, whereas the has served the genetic community well. It was a surprising source — studies of skeletal-muscle transgenics created to help manage and extremely skinny mice. became obese even on a stan- access increasing amounts Mice that lack a functional Lpin1 dard diet, mice that overex- of sequence data and web gene develop a condition that is pressed Lpin1 in adipose resources. The first known as lipodystrophy, which tissue only put on excess 1 publication to describe it is characterized by a severe lack of weight when they were refers to it as a “web directory” that “provides a adipose tissue. The lipin protein that fed a high-fat diet, indi- single point-of-access to a is encoded by this gene is expressed in cating an important envi- variety of gene-specific adipose tissue and skeletal muscle, ronmental contribution, information sources including and the lack of fatty tissue in lipin- which is reminiscent of web resources and RefSeq”. deficient mice is caused by a failure of human obesity. Throughout its life, adipocytes to differentiate. Jack Phan The authors then LocusLink was continuously updated to inform us not only and Karen Reue had previously shown showed that the causes of about the sequence and that lipin deficiency prevents mice excessive weight gain associ- function of an increasing from becoming obese, and that this ated with increased lipin levels number of species but also works both for mice that are overfed were mediated by different path- about the correct gene and those that are genetically predis- ways in the two types of transgenic nomenclature. So why did it posed to obesity. This led them to mouse. Animals that overexpress have to go, and what of its wonder whether reversing the situa- Lpin1 in adipose tissue showed replacement? In fact, it might be better to tion by increasing lipin levels would increased activation of genes that are view the recent events as the have the opposite effect and cause involved in the storage and produc- efficiency metamorphosis of LocusLink mice to become obese. tion of fat. By contrast, the weight- in the conver- rather than its demise, as To test this, they made trans- gain mechanism of transgenics with sion of food to body mass Entrez Gene incorporates all genic mice that overexpressed Lpin1 overexpressed Lpin1 in skeletal muscle and a reduced ability to use stored of the LocusLink data and can either in adipose tissue or in skeletal was associated with defects in energy body fat as an energy source. This be thought of as its enhanced extension. It provides a unified muscle. In both cases, increased Lpin1 expenditure, including an increased was also reflected at the molecular look and feel for gene-specific information and contains data for many more species, GENE EXPRESSION including mitochondrial and plastid genome data for more than a half of them. Entrez Gene has some Transcriptional silencing: the third way important additional functionality — for example, it Transcriptional silencing has until Driven by a lack of consensus on present at the promoters of can display information about now been explained by one of two the molecular mechanisms of silenced loci, should be absent splice variants, intron/exon ′ organization and a wealth of models: the first claimed that RNA transcriptional silencing in yeast, from their 3 ends. Chen and data on protein–protein polymerase or activating factors Chen and Widom quantitatively Widom used silenced URA3 to interactions. The ‘search’ are prevented from accessing their tested the two prevailing models. scrutinize RNA polymerase II function is much improved — targets owing to conformational First, by engineering the yeast occupancy; chromatin for example, one or more changes in silenced chromatin; the chromosome 3 to contain immunoprecipitation revealed species or taxonomic groups second placed the transcriptional appropriate recognition sites, the that there was much less RNA of interest can be used to block further downstream, after authors quantified the accessibility polymerase II at either the restrict the queries. Moreover, the transcription pre-initiation of DNA targets to foreign reporter promoter or the 3′ end of the query parameters can be complex has formed. Elegant proteins, including the site-specific silenced URA3 when compared saved and results sent to you by means of the ‘My NCBI’ work by Chen and Widom DNA-binding protein LexA, with the euchromatic locus, function, as information is now shows that neither is likely in vivo. They found no evidence indicating that transcription updated. The king is dead, to be correct. Their results of reduced binding to silenced loci is blocked before polymerase is long live the king! support a third model, in which that would indicate involvement of recruited. These results were Magdalena Skipper transcriptional silencing occurs steric hindrance, so discounting further confirmed when the REFERENCE 1Maglott, D. R. et al. by preventing the formation of the first model. transcription factors TFIIB and NCBI’s LocusLink and RefSeq. stable pre-initiation complexes at According to the second model, TFIIE, both of which are recruited Nucleic Acids Res. 28, 126–128 silenced promoters. RNA polymerase II, although to the pre-initiation complex, were (2000) 162 | MARCH 2005 | VOLUME 6 www.nature.com/reviews/genetics © 2005 Nature Publishing Group .

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