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Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes

Transcriptional enhancers are critical for maintaining cell-type–specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been ter...

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Autores principales: Moorthy, Sakthi D., Davidson, Scott, Shchuka, Virlana M., Singh, Gurdeep, Malek-Gilani, Nakisa, Langroudi, Lida, Martchenko, Alexandre, So, Vincent, Macpherson, Neil N., Mitchell, Jennifer A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287230/
https://www.ncbi.nlm.nih.gov/pubmed/27895109
http://dx.doi.org/10.1101/gr.210930.116
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author Moorthy, Sakthi D.
Davidson, Scott
Shchuka, Virlana M.
Singh, Gurdeep
Malek-Gilani, Nakisa
Langroudi, Lida
Martchenko, Alexandre
So, Vincent
Macpherson, Neil N.
Mitchell, Jennifer A.
author_facet Moorthy, Sakthi D.
Davidson, Scott
Shchuka, Virlana M.
Singh, Gurdeep
Malek-Gilani, Nakisa
Langroudi, Lida
Martchenko, Alexandre
So, Vincent
Macpherson, Neil N.
Mitchell, Jennifer A.
author_sort Moorthy, Sakthi D.
collection PubMed
description Transcriptional enhancers are critical for maintaining cell-type–specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes.
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spelling pubmed-52872302017-08-01 Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes Moorthy, Sakthi D. Davidson, Scott Shchuka, Virlana M. Singh, Gurdeep Malek-Gilani, Nakisa Langroudi, Lida Martchenko, Alexandre So, Vincent Macpherson, Neil N. Mitchell, Jennifer A. Genome Res Research Transcriptional enhancers are critical for maintaining cell-type–specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes. Cold Spring Harbor Laboratory Press 2017-02 /pmc/articles/PMC5287230/ /pubmed/27895109 http://dx.doi.org/10.1101/gr.210930.116 Text en © 2017 Moorthy 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 Research
Moorthy, Sakthi D.
Davidson, Scott
Shchuka, Virlana M.
Singh, Gurdeep
Malek-Gilani, Nakisa
Langroudi, Lida
Martchenko, Alexandre
So, Vincent
Macpherson, Neil N.
Mitchell, Jennifer A.
Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
title Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
title_full Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
title_fullStr Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
title_full_unstemmed Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
title_short Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
title_sort enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287230/
https://www.ncbi.nlm.nih.gov/pubmed/27895109
http://dx.doi.org/10.1101/gr.210930.116
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