Transcriptional regulation by 2,3,7,8-tetrachlorodibenzo-ρ-dioxin within the human polymorphic hs1,2 enhancer (42.7)

Abstract

Abstract The environmental contaminant 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) inhibits Ig expression and secretion. Within the IgH gene, the 3’IgH regulatory region (3’IgHRR) has been identified as a transcriptional target of TCDD. TCDD inhibits mouse 3’IgHRR and induces aryl hydrocarbon receptor (AhR) binding to dioxin response elements (DREs) within the hs1,2 and hs4 enhancers. The human hs1,2 enhancer is polymorphic due to the presence of one to four invariant sequences (IS) which have been correlated with several autoimmune disorders. Interestingly, TCDD inhibits the transcriptional activity of the mouse hs1,2 enhancer, while the human polymorphic hs1,2 enhancer activity is increased. Several transcription factor binding sites are located within both the mouse and human hs1,2 enhancers, while others are only in the mouse or human. Thus, we hypothesize that the specific transcription factor within the mouse and the human enhancers lead to differential effects by TCDD. Our data show that insertion of Pax5, deletion of the whole IS, or mutation of the AP-1/Ets site outside the IS decreases overall transcriptional activity. However, mutation of the transcription factor binding sites within the IS or the Oct site outside the IS increase the transcriptional activity. These results underscore the complexity of the transcriptional regulation of the hs1,2 enhancer and suggest an interaction between multiple transcription factors, many of which have been shown to be modulated by TCDD.