Distant sequences which regulate globin genes.

Besides the major cap site, transcription of the human epsilon-globin gene initiates at several upstream sites, the furthest 4.5 kb away. The upstream initiation sites occur in regions of hypersensitivity to DNaseI. There is also a very prominent DNaseI hypersensitive site 6.5 kb upstream which corresponds to an unusual nucleotide sequence. Upstream promoters, particularly one 200 bp upstream can be regulated independently of the major cap site. This site behaves as if it were a unidirectional enhancer. A fragment upstream of the mouse beta-globin promoter acts as a negative regulator in cis; it contains a long stretch of alternating purine and pyrimidine bases. The significance of upstream regulatory sequences adjacent to globin genes is discussed.