We study how enhancers activate transcription in the chromatin environment of eukaryotic cells. We used stably maintained minichromosomes in erythroid K562 cells to study the interaction of human globin genes and elements of the beta-globin locus control region (LCR). Promoter chromatin remodeling and transcription activation of the embryonic epsilon-globin gene is dependent on DNase I hypersensitive site 2 (HS2) of the LCR in this system. To further understand the basis for enhancer-promoter communication we mutated the reiterated transcription factor binding sites in the HS2 enhancer and in the epsilon-globin promoter. We observed, in part, that enhancer and promoter structures mutually affected each other. Not only did HS2 need to form its nuclease sensitive structure in order to remodel the promoter and activate transcription, but mutations at the GATA and CACC motifs in the promoter had an effect on the formation HS2. HS2 structure was also different in the absence of a linked globin gene. Furthermore, promoter remodeling and transcription activation by HS2 required an intact TATA box in the promoter. These observations support a direct interaction between the enhancer and the promoter when transcription is activated, and also indicate that for a distant enhancer such as the beta-globin LCR, promoter remodeling and transcription activation appear to be mechanistically linked. We continue to explore the regulatory role in vivo of chromatin structure in the expression of globin genes, and the mechanism of action of the beta- globin LCR.