title: Calculating the statistical significance of physical clusters of co-regulated genes in the genome: the role of chromatin in domain-wide gene regulation.
abstract: Physical clusters of co-regulated, but apparently functionally unrelated, genes are present in many genomes. Despite the important implication that the genomic environment contributes appreciably to the regulation of gene expression, no simple statistical method has been described to identify physical clusters of co-regulated genes. Here we report the development of a model that allows the direct calculation of the significance of such clusters. We have implemented the derived statistical relation in a software program, Pyxis, and have analyzed a selection of Saccharomyces cerevisiae gene expression microarray data sets. We have identified many gene clusters where constituent genes exhibited a regulatory dependence on proteins previously implicated in chromatin structure. Specifically, we found that Tup1p-dependent gene domains were enriched close to telomeres, which suggested a new role for Tup1p in telomere silencing. In addition, we identified Sir2p-, Sir3p- and Sir4p-dependent clusters, which suggested the presence of Sir-mediated heterochromatin in previously unidentified regions of the yeast genome. We also showed the presence of Sir4p-dependent gene clusters bordering the HMRa heterothallic locus, which suggested leaky termination of the heterochromatin by the boundary elements. These results demonstrate the utility of Pyxis in identifying possible higher order genomic features that may contribute to gene regulation in extended domains.
authors.affiliation: Department of Molecular and Cell Biology and Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, University Private Bag, Rondebosch 7701, South Africa.
authors.forename: Cheng-Fu
authors.initials: CF
authors.lastname: Chang
authors.forename: Ka-Man
authors.initials: KM
authors.lastname: Wai
authors.forename: Hugh G
authors.initials: HG
authors.lastname: Patterton
mesh_terms: D002843:Chromatin / Q000502:physiology*; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005800:Genes, Fungal; D006655:Histone Deacetylases / Q000378:metabolism; D015233:Models, Statistical; D009687:Nuclear Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins / Q000378:metabolism; D012984:Software; D016615:Telomere / Q000235:genetics
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; D012097:Repressor Proteins; C084122:SIR3 protein, S cerevisiae; C061573:SIR4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C066502:TUP1 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases