| 摘要 |
The orphan nuclear receptors TR2 and TR4 together constitute the DNA binding core of the 540 kDa DRED complex, a putative repressor of the human embryonic e- and fetal ?-globin genes. Here the functional consequences of TR2 and TR4 germ line loss of function were examined, transgenic gain of function and dominant negative gain of function on human and murine ß-type globin gene expression throughout development, e-globin transcription responded in a manner consistent with the hypothesis that TR2/TR4 is a constitutive erythroid e-globin repressor. In contrast, parallel experiments show that TR2/TR4 is a definitive stage-selective ?-globin repressor. This developmental stage-specific, gene-selective repression of the e- and ?-globin genes by TR2/TR4 establishes, when considered in concert with the competition hypothesis, a coherent molecular rationale for hemoglobin switching (temporally specific, sequential activation of all the ß-type globin genes) during vertebrate development. |
