title: Incorporating chromatin accessibility data into sequence-to-expression modeling.
abstract: Prediction of gene expression levels from regulatory sequences is one of the major challenges of genomic biology today. A particularly promising approach to this problem is that taken by thermodynamics-based models that interpret an enhancer sequence in a given cellular context specified by transcription factor concentration levels and predict precise expression levels driven by that enhancer. Such models have so far not accounted for the effect of chromatin accessibility on interactions between transcription factor and DNA and consequently on gene-expression levels. Here, we extend a thermodynamics-based model of gene expression, called GEMSTAT (Gene Expression Modeling Based on Statistical Thermodynamics), to incorporate chromatin accessibility data and quantify its effect on accuracy of expression prediction. In the new model, called GEMSTAT-A, accessibility at a binding site is assumed to affect the transcription factor's binding strength at the site, whereas all other aspects are identical to the GEMSTAT model. We show that this modification results in significantly better fits in a data set of over 30 enhancers regulating spatial expression patterns in the blastoderm-stage Drosophila embryo. It is important to note that the improved fits result not from an overall elevated accessibility in active enhancers but from the variation of accessibility levels within an enhancer. With whole-genome DNA accessibility measurements becoming increasingly popular, our work demonstrates how such data may be useful for sequence-to-expression models. It also calls for future advances in modeling accessibility levels from sequence and the transregulatory context, so as to predict accurately the effect of cis and trans perturbations on gene expression.
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Pei-Chen
authors.initials: PC
authors.lastname: Peng
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Md Abul
authors.initials: MA
authors.lastname: Hassan Samee
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, Illinois; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois. Electronic address: sinhas@illinois.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sinha
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D008957:Models, Genetic; D013816:Thermodynamics
chemical_list: D002843:Chromatin