CHARACTERIZATION AND COMPARISON OF THE HUMAN AND MOUSE DIST1 ALPHA-GLOBIN COMPLEX REVEALS A TIGHTLY PACKED MULTIPLE GENE-CLUSTER CONTAININGDIFFERENTIALLY EXPRESSED TRANSCRIPTION UNITS/

In this paper, we describe the detailed analysis of about 75 kb of gen omic DNA flanking the 5' end of the mouse alpha-globin region and comp lete the transcription map of the human region. Previously, we establi shed the homology of the human and mouse alpha-globin upstream flankin g regions (alpha UFR) and characterized in detail the mouse alpha-glob in major regulatory element (alpha MRE) and the mMPG DNA repair gene. Here, we extend our analysis with the construction of a detailed restr iction map, the mapping and isolation of two nonglobin genes, named mD ist1 and mProx1, the distribution of 18 DNase hypersensitive sites (HS Ss) in erythroid and fibroblast cells, and the analysis of the mDist1, mMPG, and mProx1 expression levels in several adult tissues and durin g fetal development. In addition, the hDist1 gene is exactly localized 1.9 kb from the hMPG gene. The mapping results show that the Dist1, M PG, and Prox1 genes, to gether with the alpha-globin genes and the (al pha MRE, form a tightly packed multiple gene cluster that is 50% more compact in mouse than in human. The expression results show that each of the genes present in this locus displays a characteristic expressio n pattern in adult tissues and during fetal development. The 18 DNase HSSs observed were scattered over this region. Interestingly, all the erythroid-sensitive HSSs were associated with the Prox1 transcription unit, whereas the only two pairs of fibroblast-sensitive HSSs present in this locus were located in the promoter regions of the mProx1 and m Dist1/mMPG genes. The possible role of the erythroid- and fibro-blast sensitive sites in the regulation of the mouse alpha-globin and nonglo bin gene expression is discussed. The characterization of the mouse al pha UFR identifies most, if not all, of the structural elements possib ly involved in the regulation of m alpha-globin gene expression and sh eds Light on the organization and evolution of the telomere-associated , GC-rich isochore family H3. (C) 1996 Academic Press, Inc.