Upstream elements bestow T-cell and haemopoietic progenitor-specific activity on the granzyme B promoter

Cytotoxic T cells and early haemopoietic progenitors share the expression o f a number of specific genes. Of these, granzyme B has attracted particular interest because of its role in inducing apoptosis during cytotoxic T cell -mediated target cell killing, and its potential role in the mobilisation a nd homeostasis of haemopoietic stem cells. Studies of granzyme B regulation should therefore yield valuable information concerning the molecular contr ol of these processes, and also identify elements capable of directing gene expression to two cell types of relevance to gene therapy. Here we show that proximal regulatory elements already known to direct prom oter activity in T cells are similarly active in haemopoietic progenitors. However, this activity is not strictly specific, since the promoter regions also direct low levels of reporter gene expression in fibroblasts. More im portantly, we also report the presence of two previously unidentified clust ers of DNaseI hypersensitive sites upstream from the murine granzyme B gene , and show that these regions impart both increased transcriptional activit y and the appropriate cell type specificity on the granzyme B promoter. The se upstream regulatory regions are therefore likely to play a key role in t he coordination of granzyme B expression in vivo. (C) 1999 Elsevier Science B.V. hll rights reserved.