A simplified model of the developmental control of β-globin gene transcription at the embryonic, fetal, and adult developmental stages (see Figures 5 and 6). The sequential interaction of the LCR and trans-acting factors, such as GATA and EKLF, with the promoters of the several globin genes are shown as are putative cis-acting silencers that may down-regulate expression for “switching.” Evidence for silencers is stronger for the ε-globin gene, but it has been assumed that they would also affect the γ-globin genes. Levels of expression are indicated by the lengths of the arrows above each gene. In 3 dimensions, these interactions would be represented by loops of DNA with bridging transcription and chromatin proteins between the LCR and the genes, now called active chromatin hubs. A more detailed model would include many other transcription factors, modifications of chromatin structure, and the possible role of microRNA molecules as well as many post-transcription control mechanisms. Illustration by Alice Y. Chen.