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Journal Club of Scientist-Recommended Papers: Jan 1, 2005

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Rapid analysis of the DNA-binding specificities of transcription factors with DNA microarrays. Mukherjee S, Berger MF, Jona G, Wang XS, Muzzey D, Snyder M, Young RA, Bulyk ML. Nature Genetics. 2004 Dec; 36(12):1331-9.

In this paper, the authors discuss their development of a “new DNA microarray-based technology, called protein binding microarrays” that provides for “rapid, high-throughput characterization of the in vitro DNA binding-site sequence specificities of transcription factors in a single day,” according to the abstract. The scientists found the DNA binding sites for three yeast transcription factors, and they write that “comparison of these proteins’ in vitro binding sites with their in vivo binding sites indicates that PBM-derived sequence specificities can accurately reflect in vivo DNA sequence specificities. In addition to previously identified targets, Abf1, Rap1, and Mig1 bound to 107, 90, and 75 putative new target intergenic regions, respectively, many of which were upstream of previously uncharacterized open reading frames.” By comparing sequences, the team found that several of the previously unidentified sites were highly conserved across five species of yeast; the authors predict that they are functional binding sites. The team also suggests that protein binding microarrays will be useful for tracking down cis regulatory elements as well as transcriptional regulatory networks.

Marc Vidal,Researcher, Dana-Farber Cancer Institute
Assistant Professor of Genetics, Harvard Medical School

 

Biological robustness. Hiroaki Kitano. Nature Rev. Genetics. 2004; 5: 826-837.

Robustness of cellular functions. Jörg Stelling, Uwe Sauer, Zoltan Szallasi, Francis J. Doyle, II and John Doyle. Cell. 2004; 118: 675-685.

The reviews by Kitano and Stelling, et. al., elegantly summarize very large sets of data and theory testing around biological robustness: the property that allows a system to remain unchanged in the face of external and internal perturbations. That cellular systems can even begin to approach such a state, let alone maintain it for extended periods of time, is quite remarkable, especially when the system operates with “unreliable components” in highly “unpredictable environments” (Kitano). The ability to keep the system as it is designed is what underlies the maintenance of health; that is, if the system is not flawed from the outset. Similar attempts at robustness would be expected from the get-go in flawed systems (i.e., somatic mutations in hereditary diseases) or when the system acquires multiple changes over time (random mutations). To make the system even more remarkable in its operation is that the same component parts involved in robustness are also those used to enable the system to evolve over time.

The impact of these principles on health maintenance, disease progression, drug discovery, and the development of systems biology modeling cannot be overstated. Understanding how these principles come together within a dynamic system adds an additional layer of complexity that will need to be incorporated into any model.

Gary Keil
Technology Analyst
Global Sciences and Information
AstraZeneca

 

High-Resolution Global Profiling of Genomic Alterations with Long Oligonucleotide Microarray. Brennan, C., Zhang, Y., Leo, C., Feng, B., Cauwels, C., Aguirre, A. J., Kim, M., Protopopov, A., and Chin, L. (2004). Cancer Res. 64, 4744-4748

 

In this paper, the authors describe their work using a commercially available array with 60-mer oligonucleotides as well as assay conditions and bioinformatics tools they developed to detect “single-copy difference in gene dosage of full complexity genomic DNA while offering high resolution,” they write in the abstract. This research enables, they add, “high-resolution genome-wide array-comparative genome hybridization profiling of human and mouse tumors” to help track down the multiple regional insertions and deletions common to genomic sites of interest for oncology researchers.

The authors believe this effort could have an immediate impact in the field. “The commercial availability of the microarrays and associated reagents, along with the technical protocols and analytical tools described in this report, should provide investigators with the immediate capacity to perform DNA analysis of normal and diseased genomes in a global and detailed manner,” according to the abstract.

Michael Metzker
Assistant Professor
Baylor College of Medicine

 

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