CCGS researcher and Biology faculty member Jason Lieb has teamed up with Vishwanath Iyer from the University of Texas at Austin to land a $1.3M technology development grant from the National Human Genome Research Institute (NHGRI). The award was made as part of the ENCODE (ENCyclopedia Of DNA Elements) Project, which aims to identify all the functional elements in the human genome sequence.

The completion of the human genome project in April 2003 is unequivocally a significant milestone toward understanding human biology and disease. An even greater challenge lies ahead as scientists attempt to translate the three-billion-letter sequence into meaningful, functional parts. Such a complete catalog or “parts list” would define all the protein-coding genes, non-protein-coding genes, transcriptional regulatory elements, sequences that mediate chromosome structure and dynamics, in addition to any new functional elements that have yet to be discovered.

In September 2003, the NHGRI officially launched the ENCODE Project to create a highly interactive public research consortium that would carry out a pilot project for testing and comparing various methods to identify functional sequences in DNA. The pilot project is focused on a limited region (30 megabases or 1%) that was selected to provide a representative cross-section of the genome. In parallel with this pilot project is a technology development component charged with devising new experimental and computational tools that would improve upon existing technologies.

The three-year grant awarded to Iyer (PI) and Lieb (co-PI) in October 2004 addresses this need for new experimental technologies. Iyer’s group is developing a novel high-throughput method for identifying protein-binding loci throughout the genome. This method, referred to as STAGE (Sequence Tag Analysis of Genomic Enrichment), is based on sequence-tag analysis of DNA recovered after chromatin immunoprecipitation. STAGE has the potential to overcome some of the limitations of whole-genome tiling microarrays that are currently available or under development for large genomes.

The Lieb group is developing a procedure for purifying and identifying all active regulatory elements from total chromatin without the requirement for antibodies or affinity tags (termed FAIRE, for Formaldehyde-Assisted Isolation of Regulatory Elements). FAIRE is hypothesized to work by exploiting a common feature of active regulatory regions: chromatin in which nucleosomes have been disrupted. Progress in isolating and identifying functional regulatory elements has been hampered by the inability of current methods to identify such common features among all regulatory elements.

STAGE and FAIRE are highly complementary approaches that have the potential to accelerate identification of protein-binding sites and regulatory elements throughout any sequenced genome. Much of the analysis of the human genome thus far has focused, understandably, on the annotation of protein-coding genes. However, these make up only a tiny fraction (~1.5%) of the entire genome. Annotating the other 98.5% will be critical in understanding how genes actually work (e.g., turn on or off), how chromosomes work (e.g., replicate, segregate, repair) and ultimately how cells work in the context of an organism. The tools that Lieb and Iyer are developing will begin to address this significant challenge, and hopefully aid scientists in extracting and harnessing all the information encrypted within the genome.

For more information, see:

Article describing ENCODE project aims, Science 306:636-640
Iyer lab website
Lieb lab website

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