A long-range flexible billboard model of gene activation

Abstract

Gene regulation is fundamentally important for the coordination of diverse biologic processes including homeostasis and responses to developmental and environmental stimuli. Transcription factor (TF) binding sites are one of the major functional subunits of gene regulation. They are arranged in cis-regulatory modules (CRMs) that can be more active than the sum of their individual effects. Recently, we described a mechanism of glucocorticoid (GC)-induced gene regulation in which the glucocorticoid receptor (GR) binds coordinately to multiple CRMs that are 10s of kilobases apart in the genome. In those results, the minority of GR binding sites appear to involve direct TF:DNA interactions. Meanwhile, other GR binding sites in a cluster interact with those direct binding sites to tune their gene regulatory activity. Here, we consider the implications of those and related results in the context of existing models of gene regulation. Based on our analyses, we propose that the billboard and regulatory grammar models of cis-regulatory element activity be expanded to consider the influence of long-range interactions between cis-regulatory modules.

Keywords: billboard; chromatin looping; gene regulation; glucocorticoid; regulatory grammar; transcription.

Figure 1.

Models of coordinated TF function. (A) The regulatory grammar model, in which functional CRMs have a defined syntax that governs their function. (B) The flexible billboard model, in which CRM regulatory element composition rather than regulatory element ordering determines function. (C) The long-range flexible billboard model, in which CRMs with flexible ordering interact with other regulatory elements via long-range interactions to coordinate target gene expression.

Figure 2.

Tethering factor co-bound nuclear receptor binding sites are closer to one another than expected by chance. (A) Clusters of TF-binding sites in linear space that can be observed via ChIP-seq reflect a mixture of direct and tethered binding. Tethered binding sites tend to be closer to direct binding sites than expected by the genomic distribution of tethering factor binding. (B) Looping mechanism of TF-binding cluster formation. (C) C/EBPβ sites are closer to GR binding sites if co-bound by GR (blue) than if not co-bound (green) (19.9 kb vs. 42.9 kb; Mann–Whitney U-test p <10_-100) (D) FOXA1 sites are closer to ERα binding sites if co-bound by ERα (blue) than if not co-bound (green) (21.9 kb vs. 111.9 kb; Mann–Whitney U-test p < 10_-100).