Abstract
Abstract Distal regulatory regions control transcription by promoter interactions that are limited to a territory to avoid non-target genes. Few loci are defined with the scrutiny needed to fully understand how a territory is established, maintained and fenced off. Here we approach the human perforin gene (PRF1). First, we transferred an epigenetically silenced PRF1 within its chromosome into a rodent CTL cell line. Afterward PRF1 expression was turned on equivalently to the endogenous mouse gene without perturbing bordering genes. Ultra long-range DHS assays showed epigenetic remodeling during chromosome transfer and delineated a 150 kb territory with 16 DHS sites for PRF1. When a corresponding BAC was introduced into the CTL, transgene expression proceeded with locus control region activity dependent on 4 distal DHS sites that also protected PRF1 from transcriptional perturbations by bordering genes. Finally, differentiation of transgenic ES cells showed the area contained all regulatory domains required for developmentally appropriate PRF1 expression during in vitro lymphopoiesis. Thus, we defined a new sequence of strategies that reliably characterizes autonomous transcriptional territories in lymphocytes.
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