Summary Model

Obviously, there is still much to learn regarding the gene activation pathway, and though there are many gaps we are not deterred from proposing a general hierarchy of events. The initial pre-activation of the p-globin locus domain during erythroid differentiation in human and mouse most likely involves chromatin modifications over a region of approximately 150 kb beginning tens of kilobases upstream of the LCR and extending down to 3'HS1. This could probably best be described as a poised conformation in which the entire locus is relatively decondensed compared to a non-erythroid locus, but not quite as open as an active subdomain during gene expression. The HS at -62 and -60 in mouse and the potential human homologue at approximately -110 kb may play a role in this initial opening along with other elements in the locus (Bulger et al. 1999; Palstra et al. 2003). Intergenic transcription may be involved in setting up this initial domain through very long, S phase-specific intergenic transcription through the entire region. These changes may be involved in preventing the globin locus from associating with repressive centromeric heterochromatin. As erythroid differentiation proceeds and the globin genes become activated, non-S-phase intergenic transcription in the LCR and the developmentally appropriate active gene subdomains may promote histone replacement with variant histone H3.3 and hyperacetylation of H3, H4 and H3/K4 methylation. These modifications may allow increased factor access and additional modifications of histones in promoter regions, for example. This would promote LCR recognition of, and dynamic interaction with, the appropriately modified gene(s) while ignoring intervening, distal, or upstream genes lacking the proper conformation or modifications. The

LCR-gene complex may promote extension of the locus beyond the confines of the chromosome territory as a result of, or in order to facilitate, highly efficient transcription of the globin genes.

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