The Globin Locus Resides in a Region of Tissue Specific Open Chromatin

The ß-globin loci of human and mouse are embedded in clusters of olfactory receptor genes (Org) that are transcriptionally silent in erythroid tissues (Bulger et al. 1999, 2000). The chicken ß-globin locus is flanked on the 3' side by Orgs but has an erythroid-expressed folate receptor (FR) gene upstream (Litt et al. 2001a). General DNase I sensitivity of the ß-globin locus has been assayed at various resolutions in the mouse, human and chicken. The chicken locus which is the most highly characterized in terms of DNase I sensitivity has four genes. The chicken LCR and globin genes lie in an approximately 30kb region of open chromatin (Felsenfeld 1993; Litt et al. 2001b). Directly upstream of the LCR is a 16-kb stretch of relatively closed chromatin followed by the FR gene that is expressed in erythroid cells prior to ß-gene activation (Prioleau et al. 1999). The human locus is also in a large region of open chro-

matin, but appears to be further divided into developmentally controlled subdomains of increased sensitivity to DNase I digestion (Gribnau et al. 2000). The LCR and active genes lie in regions of hyperaccessible chromatin, while the developmentally inactive globin genes are surrounded by chromatin of intermediate sensitivity compared to a non-erythroid gene. This pattern changes during development concurrent with the gene expression pattern. The mouse locus also resides in a relatively open chromatin region that spans approximately 150 kb from upstream of the -62.5 HS to downstream of 3'HS1 (Bulger et al. 2003). Some evidence from MEL cells suggests that the mouse locus is also divided into subdomains of differential sensitivity (Smith et al. 1984). The open region upstream of the mouse LCR contains a number of Org, which raises questions as to how these genes are kept silent in erythroid cells especially in view of their proximity to the LCR, which has been shown capable of activating heterologous genes.

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