title: Identification of a variable number of tandem repeats polymorphism and characterization of LEF-1 response elements in the promoter of the IDO1 gene.
abstract: BACKGROUND
  Indoleamine 2,3-dioxygenase (IDO) catalyzes the first and rate-limiting step of the kynurenine pathway that is an important component of immunomodulatory and neuromodulatory processes. The IDO1 gene is highly inducible by IFN-γ and TNF-α through interaction with cis-acting regulatory elements of the promoter region. Accordingly, functional polymorphisms in the IDO1 promoter could partly explain the interindividual variability in IDO expression that has been previously documented.
  
  
  RESULTS
  A PCR-sequencing strategy, applied to DNA samples from healthy Caucasians, allowed us to identify a VNTR polymorphism in the IDO1 promoter, which correlates significantly with serum tryptophan concentration, controlled partially by IDO activity, in female subjects, but not in males. Although this VNTR does not appear to affect basal or cytokine-induced promoter activity in gene reporter assays, it contains novel cis-acting elements. Three putative LEF-1 binding sites, one being located within the VNTR repeat motif, were predicted in silico and confirmed by chromatin immunoprecipitation. Overexpression of LEF-1 in luciferase assays confirmed an interaction between LEF-1 and the predicted transcription factor binding sites, and modification of the LEF-1 core sequence within the VNTR repeat motif, by site-directed mutagenesis, resulted in an increase in promoter activity.
  
  
  CONCLUSIONS
  The identification of a VNTR in the IDO1 promoter revealed a cis-acting element interacting with the most downstream factor of the Wnt signaling pathway, suggesting novel mechanisms of regulation of IDO1 expression. These data offer new insights, and suggest further studies, into the role of IDO in various pathological conditions, particularly in cancer where IDO and the Wnt pathway are strongly dysregulated.
authors: Equipe d'Accueil 4483, Faculté de Médecine de Lille, UDSL, Université Lille-Nord de France, Lille, France.
authors: Marion
authors: M
authors: Soichot
authors: Benjamin
authors: B
authors: Hennart
authors: Alaa
authors: A
authors: Al Saabi
authors: Audrey
authors: A
authors: Leloire
authors: Philippe
authors: P
authors: Froguel
authors: Claire
authors: C
authors: Levy-Marchal
authors: Odile
authors: O
authors: Poulain-Godefroy
authors: Delphine
authors: D
authors: Allorge
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D007438:Introns / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014364:Tryptophan / Q000097:blood; D055815:Young Adult
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D014364:Tryptophan; D004247:DNA