Characterization of the human beta-thromboglobulin gene. Comparison with the gene for platelet factor 4.

beta-Thromboglobulin (beta TG) is a platelet alpha-granule protein that is released in large amounts following platelet activation. This protein has approximately 70% amino acid identity with another platelet alpha granule protein, platelet factor 4 (PF4), and approximately 30% identity with other members of a family of proteins encoded by the small inducible genes (SIG) that are involved in the overlapping processes of inflammation, wound repair, and coagulation. Thus, the isolated beta TG gene is of interest in that it may further increase our understanding of beta TG's biological role, the regulation of its megakaryocytic-specific nature of expression, and the evolution and divergence of the SIG family. Using a beta TG cDNA isolated from a DAMI cell cDNA library, we cloned the corresponding beta TG gene. The gene is 1,139 base pairs (bp) long, and, like other members of the SIG family, the beta TG gene is divided into 3 exons. Two major transcriptional start sites were defined by primer extension analysis of platelet RNA, and, based on the more commonly used start site, the 5'-untranslated region is 87 bp. A TATA box is present beginning 32 bp upstream to this site. The first exon contains the 5'-untranslated region as well as the signal peptide. The second exon begins 6 bp 3' to the homologous site in PF4, and the third exon begins at a position homologous to that in PF4. Interestingly, the beta TG and PF4 genes have little detectable homology in the flanking or intronic sequences. In particular, a pyrimidine tract 5' to both the rat and human PF4 genes is not present in the upstream region of the beta TG gene. Genomic Southern blot analysis suggests that, as with the PF4 gene, there are multiple copies of the beta TG gene in the human genome. Chromosomal localization using polymerase chain reaction analysis of human/hamster somatic cell hybrids demonstrated that the beta TG gene, like the PF4 gene, is located on chromosome 4. It is, therefore, possible that the beta TG and PF4 gene form a single genomic locus on chromosome 4 whose members become coordinately activated during megakaryocyte differentiation.