Open AccessAdventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition
Author(s) -
Karen M. Lower,
Jim R. Hughes,
Marco De Gobbi,
Shirley Henderson,
Vip Viprakasit,
Chris Fisher,
Anne Goriely,
Helena Ayyub,
Jackie Sloane-Stanley,
Douglas Vernimmen,
Cordelia Langford,
David Garrick,
Richard J. Gibbons,
Douglas R. Higgs
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0909331106
Subject(s) - biology , gene , synteny , genetics , genome , gene cluster , gene expression , regulatory sequence , regulation of gene expression , globin
It is well established that all of thecis -acting sequences required for fully regulated human α-globin expression are contained within a region of ≈120 kb of conserved synteny. Here, we show that activation of this cluster in erythroid cells dramatically affects expression of apparently unrelated and noncontiguous genes in the 500 kb surrounding this domain, including a gene (NME4 ) located 300 kb from the α-globin cluster. Changes inNME4 expression are mediated by physicalcis -interactions between this gene and the α-globin regulatory elements. Polymorphic structural variation within the globin cluster, altering the number of α-globin genes, affects the pattern ofNME4 expression by altering the competition for the shared α-globin regulatory elements. These findings challenge the concept that the genome is organized into discrete, insulated regulatory domains. In addition, this work has important implications for our understanding of genome evolution, the interpretation of genome-wide expression, expression-quantitative trait loci, and copy number variant analyses.