Nonlinear chromatin configurations can juxtapose widely separated elements within a genomic locus; however, it remains unclear how these structures are established and contribute to transcriptional control. A 5′‐remote locus control region (LCR) regulates the human growth hormone (hGH‐N) gene. HSI, a pituitary‐specific component of the hGH LCR, establishes a domain of polymerase II (PolII) transcription 5′ to hGH‐N. Repression of this transcriptional domain by HSI deletion or PolII blockade decreases hGH‐N expression. Here, we show that hGH‐N activation is accompanied by positioning of the hGH‐N promoter to this LCR transcriptional domain. Selectively blocking LCR transcription inhibits the formation of this active ‘looped’ conformation. Thus, HSI is crucial for establishing a domain of noncoding PolII transcription, and this domain is intimately linked with chromatin organization of the active hGH‐N locus. This integration of LCR transcription with chromatin reconfiguration constitutes a robust pathway for long‐range gene activation.