Overexpression of FABP7 in Down syndrome fetal brains is associated with PKNOX1 gene-dosage imbalance.
Suppression subtractive hybridization performed on Down syndrome (DS) fetal brains revealed a differentially expressed gene, FABP7, mapped to 6q22-23. FABP7 overexpression in DS brains was verified by real-time PCR (1.63-fold). To elucidate the molecular basis of FABP7 overexpression and establish the relationship with chromosome 21 trisomy, the FABP7 promoter was cloned by genomic inverse PCR. Comparison to the mouse ortholog revealed conservation of reported regulatory elements, among them a Pbx/POU binding site, known to be the target of PBX heteromeric complexes. PBX partners include homeobox-containing proteins, such as PKNOX1 (PREP1), a transcription factor mapping at 21q22.3. We report here: (i) overexpression of PKNOX1 in DS fetal brains; (ii) in vitro specific binding of PKNOX1 to the Pbx/POU site of the FABP7 promoter; (iii) in vivo FABP7 promoter trans-activation in cultured neuroblastoma cells caused by PKNOX1 overexpression. To our knowledge this is the first report of a direct relation between dosage imbalance of a chromosome 21 gene and altered expression of a downstream gene mapping on another chromosome. Given the role of FABP7 in the establishment, development and maintenance of the CNS, we suggest that the overexpression of FABP7 could contribute to DS-associated neurological disorders.
Sánchez-Font
Ma Francisca
MF
Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal, 645, E-08028 Barcelona, Spain.
Bosch-Comas
Anna
A
Gonzàlez-Duarte
Roser
R
Marfany
Gemma
G
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005333:Fetus / Q000378:metabolism; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C107608:FABP7 protein, human; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C106682:PKNOX1 protein, human; D050809:POU Domain Factors; C491412:Pknox1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins