| 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 epsilon- and fetal gamma-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 beta-type globin gene expression throughout development. epsilon-globin transcription responded in a manner consistent with the hypothesis that TR2/TR4 is a constitutive erythroid epsilon-globin repressor. In contrast, parallel experiments show that TR2/TR4 is a definitive stage-selective gamma-globin repressor. This developmental stage-specific, gene-selective repression of the epsilon- and gamma-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 beta-type globin genes) during vertebrate development. |
