Abstract
The human growth hormone (hGH) gene is controlled by a long-range enhancer, HSI, located 14.5 kb 5′ to the hGH promoter. HSI establishes a domain of noncoding transcription that is ‘looped’ to the hGH promoter as an essential step in initiating hGH gene expression. Thus, defining how HSI generates its domain of noncoding transcription is central to understanding its long-range function. Here, we demonstrate that activation of noncoding transcription reflects an HSI-autonomous activity fully independent of interactions with linked gene promoters and occurring in spatial and temporal synchrony with initiation of GH expression in the embryonic pituitary. HSI establishes its noncoding transcription start sites (TSS) over a defined distance from its core determinants and in a manner independent of local primary sequences. The interval between HSI and it TSS co-maps with a domain of disordered and/or highly mobile nucleosomes specific to the pituitary locus. Thus, a localized chromatin reconfiguration by HSI and consequent establishment of an adjacent domain of noncoding transcription constitute initiating events in long-range enhancer function within the hGH locus.
Highlights
The fidelity of mammalian development is critically dependent on levels, timing, and spatial positioning of gene transcription
Our prior studies have demonstrated that HSI-dependent noncoding transcription can be fully activated on a transgene that is limited to HSI and the contiguous hCD79b gene (−8.0CD79b; Figure 1B) [23]
While this demonstrates that HSI can function independent of its cognate human growth hormone (hGH)-N promoter, it leaves open the possibility of interactions between HSI and the more proximal hCD79b promoter
Summary
The fidelity of mammalian development is critically dependent on levels, timing, and spatial positioning of gene transcription. Recent studies reveal that the extensive linear separation between an enhancer and its target promoter can be overcome via 3D reconfigurations (‘looping’) within a chromatin locus [2,3,4]. How such chromatin reconfiguration is initiated and stabilized and how it factors temporally and functionally into the overall pathway of enhancer actions remain to be more fully defined. The extent to which this enhancer-linked noncoding transcription contributes to target gene activation remains unclear. Temporal and functional linkages among enhancer-dependent noncoding transcription, chromatin reconfiguration and target gene activation remain unclear in most settings
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