Localization of distal regulatory domains in the megakaryocyte-specific platelet basic protein/platelet factor 4 gene locus

The genes for the related human (h) chemokines, PBP (platelet basic protein ) and PF4 (platelet factor 4), are within 5.3 kilobases (kb) of each other and form a megakaryocyte-specific gene locus. The hypothesis was considered that the PBP and PF4 genes share a common distal regulatory region(s) that leads to their high-level megakaryocyte-specific expression in vivo. This study examined PBP and PF4 expression in transgenic mice using 4 distinct h uman PBP/PF4 gene locus constructs. These studies showed that within the re gion studied there was sufficient information to regulate tissue-specific e xpression of both hPBP and hPF4. Indeed this region contained sufficient DN A information to lead to expression levels of PBP and PF4 comparable to the homologous mouse genes in a position-Independent, copy number-dependent fa shion. These studies also Indicated that the DNA domains that led to this e xpression were distinct for the 2 genes; hPBP expression is regulated by a region that is 1.5 to 4.4 kb upstream of that gene. Expression of hPF4 is r egulated by a region that is either intergenic between the 2 genes or immed iately downstream of the hPF4 gene. Comparison of the available human and m ouse sequences shows conserved flanking region domains containing potential mega karyocyte-related transcriptional factor DNA-binding sites. Further a nalysis of these regulatory regions may identify enhancer domains Involved In megakaryopoiesis that may be useful In the selective expression of other genes In megakaryocytes and platelets as a strategy for regulating hemosta sis, thrombosis, and inflammation.