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Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence

Modeling a gene's expression from its intergenic locus and trans-regulatory context is a fundamental goal in computational biology. Owing to the distributed nature of cis-regulatory information and the poorly understood mechanisms that integrate such information, gene locus modeling is a more c...

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Autores principales: Samee, Md. Abul Hassan, Sinha, Saurabh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945089/
https://www.ncbi.nlm.nih.gov/pubmed/24604095
http://dx.doi.org/10.1371/journal.pcbi.1003467
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author Samee, Md. Abul Hassan
Sinha, Saurabh
author_facet Samee, Md. Abul Hassan
Sinha, Saurabh
author_sort Samee, Md. Abul Hassan
collection PubMed
description Modeling a gene's expression from its intergenic locus and trans-regulatory context is a fundamental goal in computational biology. Owing to the distributed nature of cis-regulatory information and the poorly understood mechanisms that integrate such information, gene locus modeling is a more challenging task than modeling individual enhancers. Here we report the first quantitative model of a gene's expression pattern as a function of its locus. We model the expression readout of a locus in two tiers: 1) combinatorial regulation by transcription factors bound to each enhancer is predicted by a thermodynamics-based model and 2) independent contributions from multiple enhancers are linearly combined to fit the gene expression pattern. The model does not require any prior knowledge about enhancers contributing toward a gene's expression. We demonstrate that the model captures the complex multi-domain expression patterns of anterior-posterior patterning genes in the early Drosophila embryo. Altogether, we model the expression patterns of 27 genes; these include several gap genes, pair-rule genes, and anterior, posterior, trunk, and terminal genes. We find that the model-selected enhancers for each gene overlap strongly with its experimentally characterized enhancers. Our findings also suggest the presence of sequence-segments in the locus that would contribute ectopic expression patterns and hence were “shut down” by the model. We applied our model to identify the transcription factors responsible for forming the stripe boundaries of the studied genes. The resulting network of regulatory interactions exhibits a high level of agreement with known regulatory influences on the target genes. Finally, we analyzed whether and why our assumption of enhancer independence was necessary for the genes we studied. We found a deterioration of expression when binding sites in one enhancer were allowed to influence the readout of another enhancer. Thus, interference between enhancer activities was a possible factor necessitating enhancer independence in our model.
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spelling pubmed-39450892014-03-12 Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence Samee, Md. Abul Hassan Sinha, Saurabh PLoS Comput Biol Research Article Modeling a gene's expression from its intergenic locus and trans-regulatory context is a fundamental goal in computational biology. Owing to the distributed nature of cis-regulatory information and the poorly understood mechanisms that integrate such information, gene locus modeling is a more challenging task than modeling individual enhancers. Here we report the first quantitative model of a gene's expression pattern as a function of its locus. We model the expression readout of a locus in two tiers: 1) combinatorial regulation by transcription factors bound to each enhancer is predicted by a thermodynamics-based model and 2) independent contributions from multiple enhancers are linearly combined to fit the gene expression pattern. The model does not require any prior knowledge about enhancers contributing toward a gene's expression. We demonstrate that the model captures the complex multi-domain expression patterns of anterior-posterior patterning genes in the early Drosophila embryo. Altogether, we model the expression patterns of 27 genes; these include several gap genes, pair-rule genes, and anterior, posterior, trunk, and terminal genes. We find that the model-selected enhancers for each gene overlap strongly with its experimentally characterized enhancers. Our findings also suggest the presence of sequence-segments in the locus that would contribute ectopic expression patterns and hence were “shut down” by the model. We applied our model to identify the transcription factors responsible for forming the stripe boundaries of the studied genes. The resulting network of regulatory interactions exhibits a high level of agreement with known regulatory influences on the target genes. Finally, we analyzed whether and why our assumption of enhancer independence was necessary for the genes we studied. We found a deterioration of expression when binding sites in one enhancer were allowed to influence the readout of another enhancer. Thus, interference between enhancer activities was a possible factor necessitating enhancer independence in our model. Public Library of Science 2014-03-06 /pmc/articles/PMC3945089/ /pubmed/24604095 http://dx.doi.org/10.1371/journal.pcbi.1003467 Text en © 2014 Samee, Sinha http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Samee, Md. Abul Hassan
Sinha, Saurabh
Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence
title Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence
title_full Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence
title_fullStr Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence
title_full_unstemmed Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence
title_short Quantitative Modeling of a Gene's Expression from Its Intergenic Sequence
title_sort quantitative modeling of a gene's expression from its intergenic sequence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945089/
https://www.ncbi.nlm.nih.gov/pubmed/24604095
http://dx.doi.org/10.1371/journal.pcbi.1003467
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