HOT DNAs: a novel class of developmental enhancers

Abstract

Enhancers mediate localized patterns of gene expression during development. A common feature of "traditional" enhancers is the presence of clustered binding motifs for sequence-specific transcription factors (TFs). In this issue of Genes & Development, Kvon and colleagues (pp. 908-913) present new evidence that HOT (highly occupied transcription) DNAs direct specific patterns of gene expression, despite being depleted for TF-binding motifs.

Figure 1.

Comparison of a traditional enhancer and HOT enhancer. (A) Traditional enhancer. eve stripe 2; the endogenous expression pattern is shown in the inset. The eve stripe 2 enhancer is ∼480 bp and has defined transcription factor-binding sites (shown as rectangles) activators are Bcd (purple) and Hb (blue), and repressors are Kr (yellow) and Gt (green). Each transcription factor binds its corresponding recognition sequence. The integration of the Bcd and Hb activators and Gt and Kr repressors establishes stripe 2 expression in a specific location. Loss of any of the binding sites affects this pattern. For example, loss of Gt (green) repressor sites causes an anterior expansion of the normal pattern. eve 2 contains noncanonical binding sites for Zelda (Struffi et al. 2011), consistent with its proposed role as a global activator (Liang et al. 2008). (B) HOT enhancer. Blimp-1; the endogenous expression pattern is shown in the inset. The HOT DNA region found ∼9–12 kb upstream of the Blimp-1 transcription start site contains binding sites for Zelda and Trithorax-like (Trl) (GAGA). Additional, unassigned motifs are also found in this region and are depicted by the binding of μ. More than 10 other TFs (multicolored circles) are associated with this region, but the corresponding binding motifs are generally absent. This HOT region can drive GAL4 expression in three of the four Blimp-1 stripes. A bacterial artificial chromosome (BAC) construct containing ∼45 kb of genomic DNA encompassing the endogenous Blimp-1 locus gives rise to the endogenous expression pattern (not shown). However, removal of the HOT DNA results in the loss of three of the four Blimp-1 stripes. A putative traditional enhancer might drive expression of the central Blimp-1 stripe (indicated in gray).