Glucocorticoid receptor activation of the Ciz1-Lcn2 locus by long range interactions.
The cellular response to glucocorticoid receptor (GR) activation involves a highly orchestrated series of regulatory actions influenced at multiple levels by a variety of mechanisms including the action of transcription factors and chromatin modifiers. Because the majority of GR binding sites (glucocorticoid-responsive elements (GREs)) are distant from promoters, it is likely that interactions at a distance play an important role in GR action. To determine whether long range chromosomal associations play a role in transcription regulation by GR, we utilized a chromosome conformation capture-based technique (associated chromosome trap) to identify unknown, remote sequences that interact with the GR-induced Lipocalin2 (Lcn2) gene. Our screen revealed that the Lcn2 GRE interacts with the Ciz1 gene, nearly 30 kb upstream. Ciz1 was subsequently found to be a novel GR-responsive gene. The GRE proximal to the Lcn2 promoter apparently functions to regulate both the Lcn2 gene and the distal Ciz1 gene. Using quantitative chromosome conformation capture, we find that a loop structure is organized between these two genes. This structure is hormone-independent and present only in cell types where the genes are active. The strong correlation between gene expression and loop structure in different cell lines suggests that high order interactions play a role in determining tissue-specific gene regulation.
Hakim
Ofir
O
Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892-5055, USA.
John
Sam
S
Ling
Jian Qun
JQ
Biddie
Simon C
SC
Hoffman
Andrew R
AR
Hager
Gordon L
GL
D000209:Acute-Phase Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D009928:Organ Specificity / Q000502:physiology; D040641:Quantitative Trait Loci / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*
D000209:Acute-Phase Proteins; C540084:Ciz1 protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011965:Receptors, Glucocorticoid; C071332:Lcn2 protein, mouse