Abstract
Enhancers drive the gene expression patterns required for virtually every process in metazoans. We propose that enhancer length and transcription factor (TF) binding site composition—the number and identity of TF binding sites—reflect the complexity of the enhancer's regulatory task. In development, we define regulatory task complexity as the number of fates specified in a set of cells at once. We hypothesize that enhancers with more complex regulatory tasks will be longer, with more, but less specific, TF binding sites. Larger numbers of binding sites can be arranged in more ways, allowing enhancers to drive many distinct expression patterns, and therefore cell fates, using a finite number of TF inputs. We compare ~100 enhancers patterning the more complex anterior-posterior (AP) axis and the simpler dorsal-ventral (DV) axis in Drosophila and find that the AP enhancers are longer with more, but less specific binding sites than the (DV) enhancers. Using a set of ~3,500 enhancers, we find enhancer length and TF binding site number again increase with increasing regulatory task complexity. Therefore, to be broadly applicable, computational tools to study enhancers must account for differences in regulatory task.
Highlights
Every aspect of an organism, from its development to its immune response, is dependent on precise spatiotemporal control of gene expression
To understand the properties required for an enhancer to be distinguishable from the genomic background, we calculate the probability of finding an enhancer with a particular length, number of transcription factor (TF) binding sites, and average TF binding specificity (Wunderlich and Mirny, 2009) (Supplementary Material within)
Considering the median, first and third quartiles of all Drosophila TF binding specificities, the corresponding number of TF binding sites required in a 1 kb enhancer decreases from 16 to 7 to 5 as TF binding specificity increases
Summary
Every aspect of an organism, from its development to its immune response, is dependent on precise spatiotemporal control of gene expression. This control is mediated by the binding of transcription factor (TF) activators and repressors to stretches of regulatory DNA called enhancers. Given their role in diverse biological processes, it is not surprising that enhancers vary widely in architecture—length, number of TF binding sites, and the average binding specificity of the TFs that bind them. Differences in evolutionary pressures and TF cooperativity are invoked to explain why many developmental enhancers are robust to rearrangements of TF binding sites within them while some immune-responsive enhancers are intolerant to even point mutations (Thanos and Maniatis, 1995; Kim and Maniatis, 1997; Munshi et al, 2001; Arnosti and Kulkarni, 2005)
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