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Nuclear microenvironments modulate transcription from low-affinity enhancers

Tsai, Albert and Muthusamy, Anand K. and Alves, Mariana R. P. and Lavis, Luke D. and Singer, Robert H. and Stern, David L. and Crocker, Justin (2017) Nuclear microenvironments modulate transcription from low-affinity enhancers. eLife, 6 . Art. No. e28975. ISSN 2050-084X. PMCID PMC5695909. https://resolver.caltech.edu/CaltechAUTHORS:20171211-073537657

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Abstract

Transcription factors bind low-affinity DNA sequences for only short durations. It is not clear how brief, low-affinity interactions can drive efficient transcription. Here, we report that the transcription factor Ultrabithorax (Ubx) utilizes low-affinity binding sites in the Drosophila melanogaster shavenbaby (svb) locus and related enhancers in nuclear microenvironments of high Ubx concentrations. Related enhancers colocalize to the same microenvironments independently of their chromosomal location, suggesting that microenvironments are highly differentiated transcription domains. Manipulating the affinity of svb enhancers revealed an inverse relationship between enhancer affinity and Ubx concentration required for transcriptional activation. The Ubx cofactor, Homothorax (Hth), was co-enriched with Ubx near enhancers that require Hth, even though Ubx and Hth did not co-localize throughout the nucleus. Thus, microenvironments of high local transcription factor and cofactor concentrations could help low-affinity sites overcome their kinetic inefficiency. Mechanisms that generate these microenvironments could be a general feature of eukaryotic transcriptional regulation.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.7554/eLife.28975DOIArticle
https://elifesciences.org/articles/28975PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695909PubMed CentralArticle
http://datadryad.org/resource/doi:10.5061/dryad.q96g6Related ItemData Sets
ORCID:
AuthorORCID
Tsai, Albert0000-0002-1643-0780
Alves, Mariana R. P.0000-0002-0796-2101
Singer, Robert H.0000-0002-6725-0093
Stern, David L.0000-0002-1847-6483
Crocker, Justin0000-0002-5113-0476
Additional Information:© 2017 Tsai et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 26 May 2017; Accepted: 29 October 2017; Published: 02 November 2017. We thank Richard Mann, Timothée Lionnet, Paul Tillburg, and Brian English for advice and assistance on experimental design. We thank François Payre for advice on data presentation. We thank all members of the Stern and Singer labs for discussion. Albert Tsai is a Damon Runyon Fellow of the Damon Runyon Cancer Research Foundation (DRG 2220–15). Robert H Singer is supported by the 4D Nucleome Award U01-EB21236. Howard Hughes Medical Institute supported Albert Tsai, Anand K Muthusamy, Luke D Lavis, Robert H Singer, David L Stern, and Justin Crocker Mariana R P Alves and Justin Crocker are supported by the European Molecular Biological Laboratory (EMBL). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Competing interests: Robert H Singer: Reviewing editor, eLife. The other authors declare that no competing interests exist. Author contributions: Albert Tsai, Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing, Conceived and designed the experiments, Executed the experiments, Analyzed the data; Anand K Muthusamy, Resources, Provided reagents and design for live imaging experiments, Writing—review and editing; Mariana RP Alves, Investigation, Executed the experiments, Analyzed the data, Writing—review and editing; Luke D Lavis, Resources, Writing—review and editing, Provided reagents and design for live imaging experiments; Robert H Singer, Resources, Supervision, Funding acquisition, Writing—review and editing, Conceived of and designed the experiments; David L Stern, Conceptualization, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing, Conceived and Designed the experiments; Justin Crocker, Conceptualization, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing, Conceived and designed the experiments, Executed the experiments, Analyzed the data.
Funders:
Funding AgencyGrant Number
Damon Runyon Cancer Research FoundationDRG 2220-15
NIHU01-EB21236
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
European Molecular Biological Laboratory (EMBL)UNSPECIFIED
PubMed Central ID:PMC5695909
Record Number:CaltechAUTHORS:20171211-073537657
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171211-073537657
Official Citation:Tsai A, Muthusamy AK, Alves MR, et al. Nuclear microenvironments modulate transcription from low-affinity enhancers. Arnosti DN, ed. eLife. 2017;6:e28975. doi:10.7554/eLife.28975.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83782
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Dec 2017 22:43
Last Modified:03 Oct 2019 19:10

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