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Simulations of enhancer evolution provide mechanistic insights into gene regulation.

ABSTRACT: There is growing interest in models of regulatory sequence evolution. However, existing models specifically designed for regulatory sequences consider the independent evolution of individual transcription factor (TF)-binding sites, ignoring that the function and evolution of a binding site depends on its context, typically the cis-regulatory module (CRM) in which the site is located. Moreover, existing models do not account for the gene-specific roles of TF-binding sites, primarily because their roles often are not well understood. We introduce two models of regulatory sequence evolution that address some of the shortcomings of existing models and implement simulation frameworks based on them. One model simulates the evolution of an individual binding site in the context of a CRM, while the other evolves an entire CRM. Both models use a state-of-the art sequence-to-expression model to predict the effects of mutations on the regulatory output of the CRM and determine the strength of selection. We use the new framework to simulate the evolution of TF-binding sites in 37 well-studied CRMs belonging to the anterior-posterior patterning system in Drosophila embryos. We show that these simulations provide accurate fits to evolutionary data from 12 Drosophila genomes, which includes statistics of binding site conservation on relatively short evolutionary scales and site loss across larger divergence times. The new framework allows us, for the first time, to test hypotheses regarding the underlying cis-regulatory code by directly comparing the evolutionary implications of the hypothesis with the observed evolutionary dynamics of binding sites. Using this capability, we find that explicitly modeling self-cooperative DNA binding by the TF Caudal (CAD) provides significantly better fits than an otherwise identical evolutionary simulation that lacks this mechanistic aspect. This hypothesis is further supported by a statistical analysis of the distribution of intersite spacing between adjacent CAD sites. Experimental tests confirm direct homodimeric interaction between CAD molecules as well as self-cooperative DNA binding by CAD. We note that computational modeling of the D. melanogaster CRMs alone did not yield significant evidence to support CAD self-cooperativity. We thus demonstrate how specific mechanistic details encoded in CRMs can be revealed by modeling their evolution and fitting such models to multispecies data.

SUBMITTER: Duque T

PROVIDER: S-EPMC3879441 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Simulations of enhancer evolution provide mechanistic insights into gene regulation.

Duque Thyago T Samee Md Abul Hassan MA Kazemian Majid M Pham Hannah N HN Brodsky Michael H MH Sinha Saurabh S

Molecular biology and evolution 20131004 1

There is growing interest in models of regulatory sequence evolution. However, existing models specifically designed for regulatory sequences consider the independent evolution of individual transcription factor (TF)-binding sites, ignoring that the function and evolution of a binding site depends on its context, typically the cis-regulatory module (CRM) in which the site is located. Moreover, existing models do not account for the gene-specific roles of TF-binding sites, primarily because their ...[more]

PMID: 24097306

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Project description:Allostery pervades macromolecular function and drives cooperative binding of ligands to macromolecules. To decipher the mechanisms of cooperative ligand binding it is necessary to define at a microscopic level the structural and thermodynamic consequences of binding of each ligand to its allosterically coupled site(s). However, dynamic sampling of alternative conformations (microstates) in allosteric molecules complicates interpretation of both structural and thermodynamic data. Isothermal titration calorimetry has the potential to directly quantify the thermodynamics of allosteric interactions, but usually falls short of enabling mechanistic insight. This is because 1) its measurements reflect the sum of overlapping caloric processes involving binding-linked population shifts within and between microstates, and 2) data are generally fit with phenomenological binding polynomials that are underdetermined. Nevertheless, temperature-dependent binding data have the potential to resolve overlapping thermodynamic processes, while mechanistically constrained models enable hypothesis testing and identification of informative parameters. We globally fit temperature-dependent isothermal titration calorimetry data for binding of 11 tryptophan ligands to the homo-undecameric trp RNA-binding Attenuation Protein from Bacillus stearothermophilus using nearest-neighbor statistical thermodynamic models. This approach allowed us to distinguish alternative nearest-neighbor interaction models, and quantifies the thermodynamic contribution of neighboring ligands to individual binding sites. We also perform conventional Hill equation modeling and illustrate how comparatively limited it is in quantitative or mechanistic value. This work illustrates the potential of mechanistically constrained global fitting of binding data to yield the microscopic thermodynamic parameters essential for deciphering mechanisms of cooperativity in a wide range of ligand-regulated homo-oligomeric assemblies.

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Simulations of enhancer evolution provide mechanistic insights into gene regulation.

Publications

Simulations of enhancer evolution provide mechanistic insights into gene regulation.

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