Looping versus linking: toward a model for long-distance gene activation (original) (raw)

  1. Michael Bulger and
  2. Mark Groudine
  3. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 USA; Department of Radiation Oncology, University of Washington Medical School, Seattle, Washington 98195 USA

Locus control regions (LCRs) are defined by their ability, in transgenic assays, to direct high-level, tissue-specific expression of linked genes at all sites of integration examined and at moderately constant levels per gene copy. The most extensively examined LCR is that associated with the β-globin locus in mammals, where the β-globin genes reside in a linear array and are usually arranged in order of their developmental expression (Fig.). The β-globin LCR consists of several DNase I hypersensitive sites (HSs) spread over a region of 20–30 kb; the DNA sequence associated with each of the HSs contains numerous binding sites for erythroid-specific and ubiquitous transcription factors (for review, see Grosveld et al. 1993; Orkin 1995; Martin et al. 1996;Hardison et al. 1997). Expression of stably integrated β-globin transgenes in the absence of the LCR occurs only at low levels and varies depending upon the site of integration, and so is said to be subject to position effects. The high level of expression driven by the LCR at ectopic sites appears to be the product of at least two separable activities, namely the establishment of an ‘open’ chromatin domain and direct gene activation.

The human β-globin locus. Shown to scale are the human β-globin genes (red triangles) and prominent nuclease HSs (green arrows). HS1–HS5 are commonly thought to comprise the β-globin LCR, although other HS both 5′ of the LCR and 3′ of the genes are known to exist. Brackets beneath the locus describe the expression pattern of the human β-globin genes in transgenic mice. The primary site of erythroid differentiation switches from the embryonic yolk sac, to the fetal liver, to adult bone marrow during mouse development. Concomitant with this, transcription from within a transgenic human locus switches from the ε- and γ-globin genes, to the γ- …