Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.

Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins an...

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Autores principales:	Tommy Kaplan, Xiao-Yong Li, Peter J Sabo, Sean Thomas, John A Stamatoyannopoulos, Mark D Biggin, Michael B Eisen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ca16bcd2071d4059993838318aec3dd5
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spelling	oai:doaj.org-article:ca16bcd2071d4059993838318aec3dd52021-11-18T06:17:45ZQuantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.1553-73901553-740410.1371/journal.pgen.1001290https://doaj.org/article/ca16bcd2071d4059993838318aec3dd52011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21304941/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6-0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision.Tommy KaplanXiao-Yong LiPeter J SaboSean ThomasJohn A StamatoyannopoulosMark D BigginMichael B EisenPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 2, p e1001290 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Tommy Kaplan Xiao-Yong Li Peter J Sabo Sean Thomas John A Stamatoyannopoulos Mark D Biggin Michael B Eisen Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.
description	Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6-0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision.
format	article
author	Tommy Kaplan Xiao-Yong Li Peter J Sabo Sean Thomas John A Stamatoyannopoulos Mark D Biggin Michael B Eisen
author_facet	Tommy Kaplan Xiao-Yong Li Peter J Sabo Sean Thomas John A Stamatoyannopoulos Mark D Biggin Michael B Eisen
author_sort	Tommy Kaplan
title	Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.
title_short	Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.
title_full	Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.
title_fullStr	Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.
title_full_unstemmed	Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.
title_sort	quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early drosophila development.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ca16bcd2071d4059993838318aec3dd5
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Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development.

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