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Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts
Metformin is a widely-used treatment for type 2 diabetes and is reported to extend health and lifespan as a caloric restriction (CR) mimetic. Although the benefits of metformin are well documented, the impact of this compound on the function and organization of the genome in normal tissues is unclea...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441003/ https://www.ncbi.nlm.nih.gov/pubmed/30926854 http://dx.doi.org/10.1038/s41598-019-41839-1 |
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author | Gillespie, Zoe E. Wang, Chenxuan Vadan, Flaviu Yu, Topaza Y. Ausió, Juan Kusalik, Anthony Eskiw, Christopher H. |
author_facet | Gillespie, Zoe E. Wang, Chenxuan Vadan, Flaviu Yu, Topaza Y. Ausió, Juan Kusalik, Anthony Eskiw, Christopher H. |
author_sort | Gillespie, Zoe E. |
collection | PubMed |
description | Metformin is a widely-used treatment for type 2 diabetes and is reported to extend health and lifespan as a caloric restriction (CR) mimetic. Although the benefits of metformin are well documented, the impact of this compound on the function and organization of the genome in normal tissues is unclear. To explore this impact, primary human fibroblasts were treated in culture with metformin resulting in a significant decrease in cell proliferation without evidence of cell death. Furthermore, metformin induced repositioning of chromosomes 10 and 18 within the nuclear volume indicating altered genome organization. Transcriptome analyses from RNA sequencing datasets revealed that alteration in growth profiles and chromosome positioning occurred concomitantly with changes in gene expression profiles. We further identified that different concentrations of metformin induced different transcript profiles; however, significant enrichment in the activator protein 1 (AP-1) transcription factor network was common between the different treatments. Comparative analyses revealed that metformin induced divergent changes in the transcriptome than that of rapamycin, another proposed mimetic of CR. Promoter analysis and chromatin immunoprecipitation assays of genes that changed expression in response to metformin revealed enrichment of the transcriptional regulator forkhead box O3a (FOXO3a) in normal human fibroblasts, but not of the predicted serum response factor (SRF). Therefore, we have demonstrated that metformin has significant impacts on genome organization and function in normal human fibroblasts, different from those of rapamycin, with FOXO3a likely playing a role in this response. |
format | Online Article Text |
id | pubmed-6441003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64410032019-04-04 Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts Gillespie, Zoe E. Wang, Chenxuan Vadan, Flaviu Yu, Topaza Y. Ausió, Juan Kusalik, Anthony Eskiw, Christopher H. Sci Rep Article Metformin is a widely-used treatment for type 2 diabetes and is reported to extend health and lifespan as a caloric restriction (CR) mimetic. Although the benefits of metformin are well documented, the impact of this compound on the function and organization of the genome in normal tissues is unclear. To explore this impact, primary human fibroblasts were treated in culture with metformin resulting in a significant decrease in cell proliferation without evidence of cell death. Furthermore, metformin induced repositioning of chromosomes 10 and 18 within the nuclear volume indicating altered genome organization. Transcriptome analyses from RNA sequencing datasets revealed that alteration in growth profiles and chromosome positioning occurred concomitantly with changes in gene expression profiles. We further identified that different concentrations of metformin induced different transcript profiles; however, significant enrichment in the activator protein 1 (AP-1) transcription factor network was common between the different treatments. Comparative analyses revealed that metformin induced divergent changes in the transcriptome than that of rapamycin, another proposed mimetic of CR. Promoter analysis and chromatin immunoprecipitation assays of genes that changed expression in response to metformin revealed enrichment of the transcriptional regulator forkhead box O3a (FOXO3a) in normal human fibroblasts, but not of the predicted serum response factor (SRF). Therefore, we have demonstrated that metformin has significant impacts on genome organization and function in normal human fibroblasts, different from those of rapamycin, with FOXO3a likely playing a role in this response. Nature Publishing Group UK 2019-03-29 /pmc/articles/PMC6441003/ /pubmed/30926854 http://dx.doi.org/10.1038/s41598-019-41839-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gillespie, Zoe E. Wang, Chenxuan Vadan, Flaviu Yu, Topaza Y. Ausió, Juan Kusalik, Anthony Eskiw, Christopher H. Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts |
title | Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts |
title_full | Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts |
title_fullStr | Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts |
title_full_unstemmed | Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts |
title_short | Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts |
title_sort | metformin induces the ap-1 transcription factor network in normal dermal fibroblasts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441003/ https://www.ncbi.nlm.nih.gov/pubmed/30926854 http://dx.doi.org/10.1038/s41598-019-41839-1 |
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