Genes for beta-thromboglobulin and platelet factor 4 are closely linked and form part of a cluster of related genes on chromosome 4

The small inducible gene (SIG) family encodes related proteins that are involved in the overlapping processes of coagulation, inflammation, immune response, and wound repair. This family contains two branches, termed CXC and CC, which are distinguished by whether or not the first two of four conserved cysteine residues are separated by an additional amino acid residue. All of the CXC SIGs map to chromosome 4, including those encoding beta-thromboglobulin (beta TG) and platelet factor 4 (PF4), both of which are expressed by megakaryocytes in a tissue- specific fashion. Both of these latter two genes have been previously reported to be duplicated, there being a PF4 and a PF4alt gene, and a beta TG1 and beta TG2 gene. We now show by pulse-field gel electrophoresis (PFGE) that the beta TG genes are closely linked to the PF4 genes and to other previously mapped CXC SIGs, namely IL8 (encoding interleukin-8), GRO1 (encoding a cytokine also called melanoma growth- stimulatory activity), and two related genes GRO2 and GRO3, on a single 700-kb Sfil fragment localized to chromosome bands 4q12-q13. The only CXC SIG not linked to this cluster is that encoding gamma-interferon- induced 10-Kd protein (INP10), which has been previously localized to 4q21. Analysis of lambda genomic clones demonstrate that the beta TG1 and PF4 genes are separated by less than 7 kb, and the beta TG2 and PF4alt genes by approximately 5 kb. Within each beta TG/PF4 duplication, the beta TG-like gene is upstream of its linked PF4-like gene. Thus, the beta TG/PF4 genes appear to form a close-linked complex expressed in a megakaryocyte-specific fashion. Further genomic studies may provide additional insights into the regulation of the tissue- specific expression of the beta TG/PF4 gene complex, while further analysis of the linked CXC SIG cytokine family may provide further understanding of their evolutionary history.