GREAT improves functional interpretation of cis-regulatory regions

We developed the Genomic Regions Enrichment of Annotations Tool to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome

Cory Y McLean; Dave Bristor; Michael Hiller; Shoa L Clarke; Bruce T Schaar; Craig B Lowe; Aaron M Wenger; Gill Bejerano


Scholarcy highlights

  • A typical analysis, one compares the total fraction of genes annotated for a given ontology term with the fraction of annotated genes picked by proximal binding events to obtain a gene-based P value for enrichment
  • Because we still lack precise empirical maps, Genomic Regions Enrichment of Annotations Tool assigns each gene a regulatory domain consisting of a basal domain that extends 5 kb upstream and 1 kb downstream from its transcription start site, and an extension up to the basal regulatory domain of the nearest upstream and downstream genes within 1 Mb
  • GREAT is a new-generation tool aimed at the interpretation of genome-wide cis-regulatory data sets
  • It explicitly models the vertebrate cis-regulatory landscape through the use of long-range regulatory domains and a genomic region–based enrichment test, allowing analyses that take into consideration the large number of binding events that occur far beyond proximal promoters
  • By accounting for the length of gene regulatory domains, GREAT is able to highlight biologically meaningful terms and their associated cis-regulatory regions and genes, in a manner that remains robust if there are false associations between input regions and genes
  • These regulatory-domain definitions can naturally incorporate future results from three-dimensional conformation capture studies, radiation hybrid maps and other emerging approaches for measuring the regulatory genome in action. By coupling this methodology with many ontologies that span a wealth of biological information types, GREAT produces specific, accurate enrichments that provide insight into the biological roles of cis-regulatory data sets of interest
  • 4. kπ is the number of genomic regions in the foreground set that lie within the regulatory domain of some gene annotated with term π

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