Genome-Wide Association for HIV on the Trail of Transcription Factors

R esearch highlights

t E C H N O LO Gy On the trail of transcription factors

Recently developed techniques such transcription factors. For each tran- as chromatin immunoprecipitation scription factor fused to Sir4, they Using this coupled to DNA microarray analysis used a Ty5 element that was engi- method, they (ChIP–chip) or ChIPseq, in which neered to contain a short sequence were able immunoprecipitated DNA fragments that could function as a ‘barcode’ (or are sequenced using a ‘next-generation ‘calling card’, as the authors propose) to mark — sequencing’ technology, allow the specific for that factor. through Ty5 identification of any DNA sequence Following cell transformation integration that is bound by a specific protein. (with a plasmid carrying the fusion — the DNA But is it possible to do the opposite gene and another carrying the sequences and identify which proteins bind a corresponding Ty transposon) and that were certain sequence? A recent study in induction of transposition, the DNA yeast offers a promising approach to of the cells selected for the transposi- ‘visited’ by tackle this question. tion events was harvested, amplified transcription The retrotransposon Ty5 encodes and analysed by DNA sequencing factors. an integrase that interacts with the or DNA microarray hybridization. robust; moreover, it identified both silent information regulator 4 (Sir4) The authors tested the method first known and unknown genomic targets. chromatin component and catalyses by using two transcription factors, Implementing this technology for its insertion into the yeast genome, Gal4 and Gcn4, independently, then all of the ~200 yeast DNA-binding near Sir4-binding sites. The authors together with five other transcrip- proteins could allow the whole yeast took advantage of the fact that fusing tion factors, each fused to Sir4 along transcription factor network to be DNA-binding proteins to Sir4 directs with its corresponding Ty5 element. dissected in a single experiment. Ty5 integration close to the binding Analysis of three specific promoters Francesca Pentimalli sites of these proteins. Using this revealed that each had only the method, they were able to mark barcode corresponding to the tran- ORIGINAL RESEARCH PAPER Wang, H., Johnston, M. & Mitra, R. D. Calling cards for DNA- — through Ty5 integration — the scription factor that was known to binding proteins. Genome Res. 17, 1202–1209 (2007) DNA sequences that were ‘visited’ by bind it, indicating that the method is

hu m an gene t ics of seven SNPs that include regulatory regions for the RNA polymerase subunit zinc ribbon domain-containing protein 1 (ZNRD1) and the coding region of the ring finger protein RNF39. Genome-wide association for HIV As the identified SNPs also associate with ZNRD1 expression, the authors suggest that this is the Following HIV1 infection, the levels of virus itself cannot distinguish between HCP5 and most likely cause of the protective phenotype, circulating in the plasma (viral load) and the HLA-B as possible causal agents, and that HCP5 possibly through an interaction with HIV time until the onset of AIDS vary considerably itself is a good candidate for also contributing transcription. between individuals. A recent genome-wide to viral control. This is because HCP5 is an These results confirm the importance of the association study (GWAS) has uncovered two endogenous retroviral element with homology MHC region in HIV restriction, and they also polymorphisms that account for 14.1% of the to the HIV pol gene that is expressed in suggest new targets for both therapy and vaccine variation in viral load, and one polymorphism that lymphocytes, and because patients with this development. The mechanisms by which HCP5 is implicated in time until the onset of disease. haplotype continue to have reduced viral load and ZNRD1 interact with HIV could be exploited The authors carefully selected 486 patients after the virus has mutated to escape being therapeutically. Conversely, the role of HLA-C with suitable steady-state viral load for their targeted by lymphocytes. in the interaction between T cells and the virus 500k SNP study, and found three polymorphisms The second polymorphism is in the HLA-C gene could be exploited for vaccines. that associated with the phenotypes at genome- and explains 6.5% of the variation in viral load. Patrick Goymer wide significance levels. The first polymorphism, This variant is also significantly associated with explaining 9.6% of the variance in viral load, increased HLA-C expression levels, both in the ORIGINAL RESEARCH PAPER Fellay, J. et al. A whole- was in the major histocompatibility gene HLA authors’ data and in previously published results, genome association study of major determinants for host control of HIV-1. Science 19 July 2007 (doi:10.1126/ complex P5 (HCP5). The variant is in strong leading the authors to suggest that it science.1143767) linkage disequilibrium with an allele of HLA-B is the changes in expression that cause the FURTHER READING Wang, W. Y. S. et al. Genome-wide that has previously been shown to have a strong protective effect. association studies: theoretical and practical concerns. effect on disease progression. The authors note, The test for association with time of disease Nature Rev. Genet. 6, 109–118 (2005) WEB SITE http://www.genome.duke.edu/centers/pg2 however, that the genetic-association evidence onset provided one significant result: a cluster