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Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations

DNA-associated proteins (DAPs) classically regulate gene expression by binding to regulatory loci such as enhancers or promoters. As expanding catalogs of genome-wide DAP binding maps reveal thousands of loci that, unlike the majority of conventional enhancers and promoters, associate with dozens of...

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Autores principales: Ramaker, Ryne C., Hardigan, Andrew A., Goh, Say-Tar, Partridge, E. Christopher, Wold, Barbara, Cooper, Sara J., Myers, Richard M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397867/
https://www.ncbi.nlm.nih.gov/pubmed/32616518
http://dx.doi.org/10.1101/gr.260463.119
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author Ramaker, Ryne C.
Hardigan, Andrew A.
Goh, Say-Tar
Partridge, E. Christopher
Wold, Barbara
Cooper, Sara J.
Myers, Richard M.
author_facet Ramaker, Ryne C.
Hardigan, Andrew A.
Goh, Say-Tar
Partridge, E. Christopher
Wold, Barbara
Cooper, Sara J.
Myers, Richard M.
author_sort Ramaker, Ryne C.
collection PubMed
description DNA-associated proteins (DAPs) classically regulate gene expression by binding to regulatory loci such as enhancers or promoters. As expanding catalogs of genome-wide DAP binding maps reveal thousands of loci that, unlike the majority of conventional enhancers and promoters, associate with dozens of different DAPs with apparently little regard for motif preference, an understanding of DAP association and coordination at such regulatory loci is essential to deciphering how these regions contribute to normal development and disease. In this study, we aggregated publicly available ChIP-seq data from 469 human DAPs assayed in three cell lines and integrated these data with an orthogonal data set of 352 nonredundant, in vitro–derived motifs mapped to the genome within DNase I hypersensitivity footprints to characterize regions with high numbers of DAP associations. We establish a generalizable definition for high occupancy target (HOT) loci and identify putative driver DAP motifs in HepG2 cells, including HNF4A, SP1, SP5, and ETV4, that are highly prevalent and show sequence conservation at HOT loci. The number of different DAPs associated with an element is positively associated with evidence of regulatory activity, and by systematically mutating 245 HOT loci with a massively parallel mutagenesis assay, we localized regulatory activity to a central core region that depends on the motif sequences of our previously nominated driver DAPs. In sum, this work leverages the increasingly large number of DAP motif and ChIP-seq data publicly available to explore how DAP associations contribute to genome-wide transcriptional regulation.
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spelling pubmed-73978672020-08-13 Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations Ramaker, Ryne C. Hardigan, Andrew A. Goh, Say-Tar Partridge, E. Christopher Wold, Barbara Cooper, Sara J. Myers, Richard M. Genome Res Research DNA-associated proteins (DAPs) classically regulate gene expression by binding to regulatory loci such as enhancers or promoters. As expanding catalogs of genome-wide DAP binding maps reveal thousands of loci that, unlike the majority of conventional enhancers and promoters, associate with dozens of different DAPs with apparently little regard for motif preference, an understanding of DAP association and coordination at such regulatory loci is essential to deciphering how these regions contribute to normal development and disease. In this study, we aggregated publicly available ChIP-seq data from 469 human DAPs assayed in three cell lines and integrated these data with an orthogonal data set of 352 nonredundant, in vitro–derived motifs mapped to the genome within DNase I hypersensitivity footprints to characterize regions with high numbers of DAP associations. We establish a generalizable definition for high occupancy target (HOT) loci and identify putative driver DAP motifs in HepG2 cells, including HNF4A, SP1, SP5, and ETV4, that are highly prevalent and show sequence conservation at HOT loci. The number of different DAPs associated with an element is positively associated with evidence of regulatory activity, and by systematically mutating 245 HOT loci with a massively parallel mutagenesis assay, we localized regulatory activity to a central core region that depends on the motif sequences of our previously nominated driver DAPs. In sum, this work leverages the increasingly large number of DAP motif and ChIP-seq data publicly available to explore how DAP associations contribute to genome-wide transcriptional regulation. Cold Spring Harbor Laboratory Press 2020-07 /pmc/articles/PMC7397867/ /pubmed/32616518 http://dx.doi.org/10.1101/gr.260463.119 Text en © 2020 Ramaker et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Ramaker, Ryne C.
Hardigan, Andrew A.
Goh, Say-Tar
Partridge, E. Christopher
Wold, Barbara
Cooper, Sara J.
Myers, Richard M.
Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
title Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
title_full Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
title_fullStr Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
title_full_unstemmed Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
title_short Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
title_sort dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397867/
https://www.ncbi.nlm.nih.gov/pubmed/32616518
http://dx.doi.org/10.1101/gr.260463.119
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