An enhancer-titration effect induces digit-specific regulatory alleles of the HoxD cluster.
Mice carrying transgenes targeted upstream the HoxD cluster display abnormal digits, with alterations resembling those obtained with loss of functions of Hoxd genes. Because the HoxD cluster remained entirely untouched by the insertional events, we investigated whether these phenotypes were induced by regulatory modifications at a distance. We report here that these targeted relocations behaved as hypomorphic alleles of the distantly located gene Hoxd13 and showed that posterior Hoxd genes located in cis with the integration site were down-regulated. Genetic analyses suggested that this down-regulation resulted from the titration of the activity of a remote located enhancer sequence. These results indicate that the transcriptional efficiency of Hoxd genes in digits could be modulated by the presence of other, unrelated, promoters, within the regulatory landscape of this enhancer. Modifications in these latter transcription units may thus impact upon digit morphology, through misregulation of Hoxd genes, thus illustrating the "buffering effect" that such a global regulatory element can exert upon a short genomic interval.
Monge
Ignacio
I
Department of Zoology and Animal Biology and NCCR Frontiers in Genetics, University of Geneva, Sciences III, Quai Ernest Ansermet 30,1211 Geneva 11, Switzerland.
Kondo
Takashi
T
Duboule
Denis
D
D000818:Animals; D005314:Embryonic and Fetal Development / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D005809:Genes, Regulator; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors
D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D014157:Transcription Factors