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Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification

Cis-regulatory modules (CRMs) are defined by unique combinations of transcription factor-binding sites. Emerging evidence suggests that the number, affinity, and organization of sites play important roles in regulating enhancer output and, ultimately, gene expression. Here, we investigate how the ci...

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Autores principales: Boisclair Lachance, Jean-François, Webber, Jemma L., Hong, Lu, Dinner, Aaron R., Rebay, Ilaria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900712/
https://www.ncbi.nlm.nih.gov/pubmed/29535190
http://dx.doi.org/10.1101/gad.307132.117
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author Boisclair Lachance, Jean-François
Webber, Jemma L.
Hong, Lu
Dinner, Aaron R.
Rebay, Ilaria
author_facet Boisclair Lachance, Jean-François
Webber, Jemma L.
Hong, Lu
Dinner, Aaron R.
Rebay, Ilaria
author_sort Boisclair Lachance, Jean-François
collection PubMed
description Cis-regulatory modules (CRMs) are defined by unique combinations of transcription factor-binding sites. Emerging evidence suggests that the number, affinity, and organization of sites play important roles in regulating enhancer output and, ultimately, gene expression. Here, we investigate how the cis-regulatory logic of a tissue-specific CRM responsible for even-skipped (eve) induction during cardiogenesis organizes the competing inputs of two E-twenty-six (ETS) members: the activator Pointed (Pnt) and the repressor Yan. Using a combination of reporter gene assays and CRISPR–Cas9 gene editing, we suggest that Yan and Pnt have distinct syntax preferences. Not only does Yan prefer high-affinity sites, but an overlapping pair of such sites is necessary and sufficient for Yan to tune Eve expression levels in newly specified cardioblasts and block ectopic Eve induction and cell fate specification in surrounding progenitors. Mechanistically, the efficient Yan recruitment promoted by this high-affinity ETS supersite not only biases Yan–Pnt competition at the specific CRM but also organizes Yan-repressive complexes in three dimensions across the eve locus. Taken together, our results uncover a novel mechanism by which differential interpretation of CRM syntax by a competing repressor–activator pair can confer both specificity and robustness to developmental transitions.
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spelling pubmed-59007122018-09-01 Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification Boisclair Lachance, Jean-François Webber, Jemma L. Hong, Lu Dinner, Aaron R. Rebay, Ilaria Genes Dev Research Paper Cis-regulatory modules (CRMs) are defined by unique combinations of transcription factor-binding sites. Emerging evidence suggests that the number, affinity, and organization of sites play important roles in regulating enhancer output and, ultimately, gene expression. Here, we investigate how the cis-regulatory logic of a tissue-specific CRM responsible for even-skipped (eve) induction during cardiogenesis organizes the competing inputs of two E-twenty-six (ETS) members: the activator Pointed (Pnt) and the repressor Yan. Using a combination of reporter gene assays and CRISPR–Cas9 gene editing, we suggest that Yan and Pnt have distinct syntax preferences. Not only does Yan prefer high-affinity sites, but an overlapping pair of such sites is necessary and sufficient for Yan to tune Eve expression levels in newly specified cardioblasts and block ectopic Eve induction and cell fate specification in surrounding progenitors. Mechanistically, the efficient Yan recruitment promoted by this high-affinity ETS supersite not only biases Yan–Pnt competition at the specific CRM but also organizes Yan-repressive complexes in three dimensions across the eve locus. Taken together, our results uncover a novel mechanism by which differential interpretation of CRM syntax by a competing repressor–activator pair can confer both specificity and robustness to developmental transitions. Cold Spring Harbor Laboratory Press 2018-03-01 /pmc/articles/PMC5900712/ /pubmed/29535190 http://dx.doi.org/10.1101/gad.307132.117 Text en © 2018 Boisclair Lachance 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://genesdev.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 Paper
Boisclair Lachance, Jean-François
Webber, Jemma L.
Hong, Lu
Dinner, Aaron R.
Rebay, Ilaria
Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
title Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
title_full Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
title_fullStr Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
title_full_unstemmed Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
title_short Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
title_sort cooperative recruitment of yan via a high-affinity ets supersite organizes repression to confer specificity and robustness to cardiac cell fate specification
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900712/
https://www.ncbi.nlm.nih.gov/pubmed/29535190
http://dx.doi.org/10.1101/gad.307132.117
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