Cargando…

Heterogeneity of transcription factor binding specificity models within and across cell lines

Complex gene expression patterns are mediated by the binding of transcription factors (TFs) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TF's DNA binding interaction partners, motivating genomic context-based models of TF occupancy. However, appro...

Descripción completa

Detalles Bibliográficos
Autores principales: Sharmin, Mahfuza, Bravo, Héctor Corrada, Hannenhalli, Sridhar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971765/
https://www.ncbi.nlm.nih.gov/pubmed/27311443
http://dx.doi.org/10.1101/gr.199166.115
_version_ 1782446167073751040
author Sharmin, Mahfuza
Bravo, Héctor Corrada
Hannenhalli, Sridhar
author_facet Sharmin, Mahfuza
Bravo, Héctor Corrada
Hannenhalli, Sridhar
author_sort Sharmin, Mahfuza
collection PubMed
description Complex gene expression patterns are mediated by the binding of transcription factors (TFs) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TF's DNA binding interaction partners, motivating genomic context-based models of TF occupancy. However, approaches thus far have assumed a uniform TF binding model to explain genome-wide cell-type–specific binding sites. Therefore, the cell type heterogeneity of TF occupancy models, as well as the extent to which binding rules underlying a TF's occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble-based approach (TRISECT) to identify the heterogeneous binding rules for cell-type–specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-seq data in four to 12 different cell types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy. Importantly, many of the binding rules derived from individual cell types are shared across cell types and reveal distinct yet functionally coherent putative target genes in different cell types. Closer inspection of the predicted cell-type–specific interaction partners provides insights into the context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising the interaction partners within a cell type, many of which nevertheless transcend cell types. Notably, the putative targets of shared binding rules in different cell types, while distinct, exhibit significant functional coherence.
format Online
Article
Text
id pubmed-4971765
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-49717652017-02-01 Heterogeneity of transcription factor binding specificity models within and across cell lines Sharmin, Mahfuza Bravo, Héctor Corrada Hannenhalli, Sridhar Genome Res Method Complex gene expression patterns are mediated by the binding of transcription factors (TFs) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TF's DNA binding interaction partners, motivating genomic context-based models of TF occupancy. However, approaches thus far have assumed a uniform TF binding model to explain genome-wide cell-type–specific binding sites. Therefore, the cell type heterogeneity of TF occupancy models, as well as the extent to which binding rules underlying a TF's occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble-based approach (TRISECT) to identify the heterogeneous binding rules for cell-type–specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-seq data in four to 12 different cell types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy. Importantly, many of the binding rules derived from individual cell types are shared across cell types and reveal distinct yet functionally coherent putative target genes in different cell types. Closer inspection of the predicted cell-type–specific interaction partners provides insights into the context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising the interaction partners within a cell type, many of which nevertheless transcend cell types. Notably, the putative targets of shared binding rules in different cell types, while distinct, exhibit significant functional coherence. Cold Spring Harbor Laboratory Press 2016-08 /pmc/articles/PMC4971765/ /pubmed/27311443 http://dx.doi.org/10.1101/gr.199166.115 Text en © 2016 Sharmin et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Method
Sharmin, Mahfuza
Bravo, Héctor Corrada
Hannenhalli, Sridhar
Heterogeneity of transcription factor binding specificity models within and across cell lines
title Heterogeneity of transcription factor binding specificity models within and across cell lines
title_full Heterogeneity of transcription factor binding specificity models within and across cell lines
title_fullStr Heterogeneity of transcription factor binding specificity models within and across cell lines
title_full_unstemmed Heterogeneity of transcription factor binding specificity models within and across cell lines
title_short Heterogeneity of transcription factor binding specificity models within and across cell lines
title_sort heterogeneity of transcription factor binding specificity models within and across cell lines
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971765/
https://www.ncbi.nlm.nih.gov/pubmed/27311443
http://dx.doi.org/10.1101/gr.199166.115
work_keys_str_mv AT sharminmahfuza heterogeneityoftranscriptionfactorbindingspecificitymodelswithinandacrosscelllines
AT bravohectorcorrada heterogeneityoftranscriptionfactorbindingspecificitymodelswithinandacrosscelllines
AT hannenhallisridhar heterogeneityoftranscriptionfactorbindingspecificitymodelswithinandacrosscelllines