The juxtaposition of a promoter with a locus control region transcriptional domain activates gene expression.

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.