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Coacting enhancers can have complementary functions within gene regulatory networks and promote canalization

Dunipace, Leslie and Ákos, Zsuzsa and Stathopoulos, Angelike (2019) Coacting enhancers can have complementary functions within gene regulatory networks and promote canalization. PLOS Genetics, 15 (12). Art. No. e1008525. ISSN 1553-7404. PMCID PMC6932828. https://resolver.caltech.edu/CaltechAUTHORS:20191218-141159620

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Abstract

Developmental genes are often regulated by multiple enhancers exhibiting similar spatiotemporal outputs, which are generally considered redundantly acting though few have been studied functionally. Using CRISPR-Cas9, we created deletions of two enhancers, brk5’ and brk3’, that drive similar but not identical expression of the gene brinker (brk) in early Drosophila embryos. Utilizing both in situ hybridization and quantitative mRNA analysis, we investigated the changes in the gene network state caused by the removal of one or both of the early acting enhancers. brk5’ deletion generally phenocopied the gene mutant, including expansion of the BMP ligand decapentaplegic (dpp) as well as inducing variability in amnioserosa tissue cell number suggesting a loss of canalization. In contrast, brk3’ deletion presented unique phenotypes including dorsal expansion of several ventrally expressed genes and a decrease in amnioserosa cell number. Similarly, deletions were made for two enhancers associated with the gene short-gastrulation (sog), sog.int and sog.dist, demonstrating that they also exhibit distinct patterning phenotypes and affect canalization. In summary, this study shows that similar gene expression driven by coacting enhancers can support distinct, and sometimes complementary, functions within gene regulatory networks and, moreover, that phenotypes associated with individual enhancer deletion mutants can provide insight into new gene functions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1371/journal.pgen.1008525DOIArticle
https://doi.org/10.1371/journal.pgen.1008525.s001DOIS1 Fig.
https://doi.org/10.1371/journal.pgen.1008525.s002DOIS2 Fig.
https://doi.org/10.1371/journal.pgen.1008525.s003DOIS3 Fig.
https://doi.org/10.1371/journal.pgen.1008525.s004DOIS4 Fig.
https://doi.org/10.1371/journal.pgen.1008525.s005DOIS5 Fig.
https://doi.org/10.1371/journal.pgen.1008525.s006DOIS6 Fig.
https://doi.org/10.1371/journal.pgen.1008525.s007DOIS1 Dataset
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932828/PubMed CentralArticle
ORCID:
AuthorORCID
Dunipace, Leslie0000-0002-1739-6537
Ákos, Zsuzsa0000-0002-4587-6212
Stathopoulos, Angelike0000-0001-6597-2036
Additional Information:© 2019 Dunipace et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: July 22, 2019; Accepted: November 15, 2019; Published: December 12, 2019. Data Availability: All relevant data are within the manuscript and its Supporting Information files. This study was supported by National Institute of Health (https://www.nigms.nih.gov/) grant R35GM118146 to A.S and American Heart Association (https://professional.heart.org/professional/ResearchPrograms/ApplicationInformation/UCM_443314_Postdoctoral-Fellowship.jsp) grant 18POST34080493 to Zs.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank Susie Newcomb for help with figures and editing of the manuscript, Jeremy Sandler for help with NanoString experiments, Zsofia Kallus and Gergely Gati for help with pMad quantification, as well as Hilary Ashe and Mike Levine for comments on the manuscript. Author Contributions: Conceptualization: Leslie Dunipace, Angelike Stathopoulos. Formal analysis: Leslie Dunipace, Zsuzsa Ákos, Angelike Stathopoulos. Funding acquisition: Angelike Stathopoulos. Investigation: Leslie Dunipace. Project administration: Angelike Stathopoulos. Supervision: Angelike Stathopoulos. Validation: Leslie Dunipace. Visualization: Leslie Dunipace, Zsuzsa Ákos.
Funders:
Funding AgencyGrant Number
NIHR35GM118146
American Heart Association18POST34080493
Issue or Number:12
PubMed Central ID:PMC6932828
Record Number:CaltechAUTHORS:20191218-141159620
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191218-141159620
Official Citation:Dunipace L, Ákos Z, Stathopoulos A (2019) Coacting enhancers can have complementary functions within gene regulatory networks and promote canalization. PLoS Genet 15(12): e1008525. https://doi.org/10.1371/journal.pgen.1008525
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100360
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Dec 2019 22:24
Last Modified:08 Jan 2020 17:44

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