Models of LCR function.

A globin gene is denoted by a green rectangular box with the promoter region indicated in a lighter green. Transcription factors are shown as colored ovals and circles. The 4 erythroid-specific hypersensitive site cores (HSs) are indicated by small red boxes. Blue boxes are the positions of 5′HS5 and 3′HS1, representing likely insulator elements. The flanking DNA sequences of the HSs are depicted as loops between the HS cores. Transcripts are denoted by wavy arrows. (A) Looping model. Transcription factors bind to the LCR HSs and the gene promoter. The LCR directly interacts with the gene promoter by looping out the intervening DNA, thus forming an active transcription complex at the gene promoter. (B) Tracking model. Sequence-specific transcription factors bind to the LCR, forming a complex that tracks down the DNA sequence, as depicted by the large black arrowhead, until encountering transcription factors bound to the appropriate gene promoter, initiating high-level gene expression. (C) Facilitated tracking model. Aspects of both looping and tracking models are combined. Sequence-specific transcription factors bind the LCR; looping then occurs to deliver the bound transcription factors proximal to the gene promoter, followed by tracking, until they encounter transcription factors bound to the appropriate gene promoter. (D) Linking model. Sequential binding of transcription factors along the DNA directs changes in chromatin conformation and defines the transcriptional domain. The transcription factors are linked to one another from the LCR to the gene promoter by non–DNA-binding proteins and chromatin modifiers (shown as small colored circles).