Research Article: A sequence level model of an intact locus predicts the location and function of nonadditive enhancers

Date Published: July 17, 2017

Publisher: Public Library of Science

Author(s): Kenneth A. Barr, John Reinitz, Michael Levine.


Metazoan gene expression is controlled through the action of long stretches of noncoding DNA that contain enhancers—shorter sequences responsible for controlling a single aspect of a gene’s expression pattern. Models built on thermodynamics have shown how enhancers interpret protein concentration in order to determine specific levels of gene expression, but the emergent regulatory logic of a complete regulatory locus shows qualitative and quantitative differences from isolated enhancers. Such differences may arise from steric competition limiting the quantity of DNA that can simultaneously influence the transcription machinery. We incorporated this competition into a mechanistic model of gene regulation, generated efficient algorithms for this computation, and applied it to the regulation of Drosophila even-skipped (eve). This model finds the location of enhancers and identifies which factors control the boundaries of eve expression. This model predicts a new enhancer that, when assayed in vivo, drives expression in a non-eve pattern. Incorporation of chromatin accessibility eliminates this inconsistency.

Partial Text

Understanding how genetic function arises from the structural properties of genes is a fundamental problem of molecular genetics. With respect to the non-coding portions of genes, in prokaryotes there is a clear relationship between chemical properties and genetic function. In the lac operon, for example, there is a one-to-one mapping between the functional genetic unit of the operator and the structural/chemical unit of the binding site for lac repressor [1]. This level of understanding is absent in metazoan genes. The expression of many such genes is under the control of cis-acting DNA sequence which can span tens [2] to hundreds of thousands [3] of nucleotides. The central feature of such genes is the presence of enhancers, also known as cis-regulatory modules (CRMs). These sequences, which typically span 500 to 1000 base pairs (bp), recruit sequence-specific transcription factors to drive a subset of a gene’s full expression pattern [4–8]. Although enhancers are ubiquitous, how they arise from the underlying structure of genes remains obscure.

The central result of this paper is the demonstration that the enhancer structure of eve arises because of competition between different regions of the proximal promoter for interaction with the basal complex (Eq (2)). The competition described may reflect kinetic statistics of interactions between distally bound adaptors and the basal complex. This competition differs from steric competition for a binding site (cf Eq S4 in S1 Appendix) in that N[m,m+α], unlike qi (Eq S6 in S1 Appendix), depends not only on thermodynamically described interactions of TFs with the DNA but also on the protein-protein interactions which convert repressors into activators by coactivation and quench activators (Eqs S14 and S16 in S1 Appendix).




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