Temporal expression of a V-H promoter-C mu transgene linked to the IgH HS1,2 enhancer

Immunoglobulin heavy chain (IgH) gene expression is guided by cis-regulator y elements which direct correct temporal and spatial expression in B lineag e cells. One of these cis-acting elements is the IgH HS1,2 enhancer and pre vious studies in transgenic mice have revealed a temporally restricted acti vity of an HS1,2 enhancer-linked human beta-globin reporter gene in B linea ge cells. To assess whether this enhancer can impose strict temporal regula tion onto a V-H-promoter-C mu reporter gene, transgenic mice were generated . These mice expressed high serum levels of protein from the transgene. Mor eover, high levels of transgene expression were observed in spleen and thym us, while lower expression was found in heart and kidney and no expression was detected in liver and brain. Interestingly, transgene expression was co nfined to large, activated B cells and peritoneal B cells but not observed in small, resting splenic B cells or activated T cells. However, upon mitog enic stimulation of resting B cells with LPS, high levels of transgene expr ession was induced. Our data demonstrate that the HS1,2 enhancer can intera ct with a natural V-H promoter in a strict temporal fashion and when provid ed with an appropriate activation signal, this V-H promoter/enhancer constr uct can induce transgene expression in resting B, but not T lineage cells. Our data are compatible with a model whereby the regulation of IgH gene exp ression may be subject to regulation by distinct subsets of cis-regulatory elements acting at different stages of B lymphocyte development. Thus, Ig g ene expression may be regulated via an interaction between the V-H promoter and 3' enhancer elements there typified by the HS1,2 enhancer) in terminal ly differentiated B lineage cells. (C) 1999 Elsevier Science Ltd. All right s reserved.