Mammalian -globin loci contain multiple genes that are activated at different developmental stages. Studies have suggested that the transcription of one gene in a locus can influence the expression of the other locus genes. The prevalent model to explain this transcriptional interference is that all potentially active genes compete for locus control region (LCR) activity. To investigate the influence of transcription by the murine embryonic genes on transcription of the other -like genes, we generated mice with deletions of the promoter regions of Ey and h1 and measured transcription of the remaining genes. Deletion of the Ey and h1 promoters increased transcription of ma-jor and minor 2-fold to 3-fold during primitive erythropoiesis. Deletion of Ey did not affect h1 nor did deletion of h1 affect Ey, but Ey deletion uniquely activated transcription from h0, a -like globin gene immediately downstream of Ey. Protein analysis showed that h0 encodes a translatable -like globin protein that can pair with alpha globin. The lack of transcriptional interference between Ey and h1 and the gene-specific repression of h0 did not support LCR competition among the embryonic genes and suggested that direct transcriptional interference from Ey suppressed h0. IntroductionThe mammalian -globin loci consist of multiple genes that are activated at different developmental stages in a tissue-specific manner. In the mouse, 2 "embryonic" -like globin genes, Ey and h1, are transcribed at high levels only during primitive erythropoiesis in the embryonic yolk sac. The "adult" expressed -type globin genes--major and -minor-are expressed at low levels in embryos and at high levels during fetal and adult definitive erythropoiesis. This developmental up-regulation of the adult -like globin genes is coincident with the silencing of the embryonic -like globin genes and is hypothesized to be mechanistically related to the silencing of the embryonic genes.Regulatory elements of each -like globin gene include a promoter and associated gene proximal cis-regulatory elements bound by multiple-tissue specific or ubiquitous transcription factors. High-level expression of all the genes at the locus requires a gene distal cis-regulatory element, the locus control region (LCR), which is located 5 to 22 kb upstream of the embryonic Ey gene in the mouse locus (for a review, see Stamatoyannopoulos and Grosveld 1 ). The role, if any, of the LCR in the developmental regulation of individual genes within the locus is unclear.Previous studies of -globin gene regulation in transgenic mice carrying portions of the human -globin locus have suggested that developmental expression of the embryonic and adult genes is regulated through different mechanisms. For the embryonic genes, the developmental silencing is gene autonomous and is achieved through binding or dissociation of specific transcription factors to or from the gene proximal cis-regulatory elements. When directly linked to the LCR, the human embryonic ⑀ is expressed only at embryo...
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