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Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene
The insulin signalling pathway is evolutionarily conserved throughout metazoans, playing key roles in development, growth, and metabolism. Misregulation of this pathway is associated with a multitude of disease states including diabetes, cancer, and neurodegeneration. The human insulin receptor gene...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461493/ https://www.ncbi.nlm.nih.gov/pubmed/37621079 http://dx.doi.org/10.1080/19336934.2023.2242238 |
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author | Thompson, Katie D. Suber, Will Nicholas, Rachel Arnosti, David N. |
author_facet | Thompson, Katie D. Suber, Will Nicholas, Rachel Arnosti, David N. |
author_sort | Thompson, Katie D. |
collection | PubMed |
description | The insulin signalling pathway is evolutionarily conserved throughout metazoans, playing key roles in development, growth, and metabolism. Misregulation of this pathway is associated with a multitude of disease states including diabetes, cancer, and neurodegeneration. The human insulin receptor gene (INSR) is widely expressed throughout development and was previously described as a ‘housekeeping’ gene. Yet, there is abundant evidence that this gene is expressed in a cell-type specific manner, with dynamic regulation in response to environmental signals. The Drosophila insulin-like receptor gene (InR) is homologous to the human INSR gene and was previously shown to be regulated by multiple transcriptional elements located primarily within the introns of the gene. These elements were roughly defined in ~1.5 kbp segments, but we lack an understanding of the potential detailed mechanisms of their regulation. We characterized the substructure of these cis-regulatory elements in Drosophila S2 cells, focusing on regulation through the ecdysone receptor (EcR) and the dFOXO transcription factor. By identifying specific locations of activators and repressors within 300 bp subelements, we show that some previously identified enhancers consist of relatively compact clusters of activators, while others have a distributed architecture not amenable to further reduction. In addition, these assays uncovered a long-range repressive action of unliganded EcR. The complex transcriptional circuitry likely endows InR with a highly flexible and tissue-specific response to tune insulin signalling. Further studies will provide insights to demonstrate the impact of natural variation in this gene’s regulation, applicable to human genetic studies. |
format | Online Article Text |
id | pubmed-10461493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-104614932023-08-29 Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene Thompson, Katie D. Suber, Will Nicholas, Rachel Arnosti, David N. Fly (Austin) Research Paper The insulin signalling pathway is evolutionarily conserved throughout metazoans, playing key roles in development, growth, and metabolism. Misregulation of this pathway is associated with a multitude of disease states including diabetes, cancer, and neurodegeneration. The human insulin receptor gene (INSR) is widely expressed throughout development and was previously described as a ‘housekeeping’ gene. Yet, there is abundant evidence that this gene is expressed in a cell-type specific manner, with dynamic regulation in response to environmental signals. The Drosophila insulin-like receptor gene (InR) is homologous to the human INSR gene and was previously shown to be regulated by multiple transcriptional elements located primarily within the introns of the gene. These elements were roughly defined in ~1.5 kbp segments, but we lack an understanding of the potential detailed mechanisms of their regulation. We characterized the substructure of these cis-regulatory elements in Drosophila S2 cells, focusing on regulation through the ecdysone receptor (EcR) and the dFOXO transcription factor. By identifying specific locations of activators and repressors within 300 bp subelements, we show that some previously identified enhancers consist of relatively compact clusters of activators, while others have a distributed architecture not amenable to further reduction. In addition, these assays uncovered a long-range repressive action of unliganded EcR. The complex transcriptional circuitry likely endows InR with a highly flexible and tissue-specific response to tune insulin signalling. Further studies will provide insights to demonstrate the impact of natural variation in this gene’s regulation, applicable to human genetic studies. Taylor & Francis 2023-08-24 /pmc/articles/PMC10461493/ /pubmed/37621079 http://dx.doi.org/10.1080/19336934.2023.2242238 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. |
spellingShingle | Research Paper Thompson, Katie D. Suber, Will Nicholas, Rachel Arnosti, David N. Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
title | Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
title_full | Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
title_fullStr | Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
title_full_unstemmed | Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
title_short | Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
title_sort | long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461493/ https://www.ncbi.nlm.nih.gov/pubmed/37621079 http://dx.doi.org/10.1080/19336934.2023.2242238 |
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