Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite.
Microsatellites are common repeated sequences, which are useful as genetic markers and lack any clearly established function. In a previous study we suggested that an intronic polymorphic TCAT repeat in the tyrosine hydroxylase (TH) gene, the microsatellite HUMTH01, may regulate transcription. The TH gene encodes the rate-limiting enzyme in the synthesis of catecholamines, and the microsatellite HUMTH01 has been used in genetic studies of neuropsychiatric and cardiovascular diseases, in which disturbances of catecholaminergic neurotransmission have been implicated. HUMTH01 alleles associated with these diseases act as transcriptional enhancers when linked to a minimal promoter and are recognized by specific nuclear factors. Here we show that allelic variations of HUMTH01 commonly found in humans have a quantitative silencing effect on TH gene expression. Two specific proteins, ZNF191, a zinc finger protein, and HBP1, an HMG box transcription factor, which bind the TCAT motif, were then cloned. Finally, allelic variations of HUMTH01 correlate with quantitative and qualitative changes in the binding by ZNF191. Thus, this repeated sequence may contribute to the control of expression of quantitative genetic traits. As the HUMTH01 core motif is ubiquitous in the genome, this phenomenon may be relevant to the quantitative expression of many genes in addition to TH.
Albanèse
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Laboratoire de Génétique de la Neurotransmission, CNRS UMR C9923, Hôpital de la Pitié Salpétrière, 83 Boulevard de l'hôpital, 75013 Paris, France.
Biguet
N F
NF
Kiefer
H
H
Bayard
E
E
Mallet
J
J
Meloni
R
R
D000483:Alleles; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D008156:Luciferases / Q000096:biosynthesis; D018895:Microsatellite Repeats / Q000235:genetics*; D016716:PC12 Cells; D011110:Polymorphism, Genetic; D023302:Protein Footprinting; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics*
D011993:Recombinant Fusion Proteins; D008156:Luciferases; D014446:Tyrosine 3-Monooxygenase