The ZFHX1A gene is differentially autoregulated by its isoforms.
The Zfhx1a gene expresses two different isoforms; the full length Zfhx1a-1 and a truncated isoform termed Zfhx1a-2 lacking the first exon. Deletion analysis of the Zfhx1a-1 promoter localized cell-specific repressors, and a proximal G-string that is critically required for transactivation. Transfection of Zfhx1a-1 cDNA, but not Zfhx1a-2, downregulates Zfhx1a-1 promoter activity. Mutation of an E2-box disrupted the binding of both Zfhx1a isoforms. Consistent with this, transfected Zfhx1a-1 does not regulate the transcriptional activity of the E-box mutated Zfhx1a-1 promoter. Competitive EMSAs and transfection assays show that Zfhx1a-2 can function as a dominant negative isoform since it is able to compete and displace Zfhx1a-1 from its binding site and overcome Zfhx1a-1 induced repression of the Zfhx1a-1 promoter in cells. Hence, the Zfhx1a-1 gene is autoregulated in part by negative feedback on its own promoter which is, in turn, modified by the availability of the negative dominant isoform Zfhx1a-2.
Manavella
Pablo A
PA
CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000 Córdoba, Argentina.
Roqueiro
Gonzalo
G
Darling
Douglas S
DS
Cabanillas
Ana M
AM
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1