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...

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Veröffentlicht in:Scientific reports 2019-03, Vol.9 (1), p.5369-17, Article 5369
Hauptverfasser: Gillespie, Zoe E., Wang, Chenxuan, Vadan, Flaviu, Yu, Topaza Y., Ausió, Juan, Kusalik, Anthony, Eskiw, Christopher H.
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container_issue 1
container_start_page 5369
container_title Scientific reports
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creator Gillespie, Zoe E.
Wang, Chenxuan
Vadan, Flaviu
Yu, Topaza Y.
Ausió, Juan
Kusalik, Anthony
Eskiw, Christopher H.
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.
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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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30926854</pmid><doi>10.1038/s41598-019-41839-1</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record>
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subjects 14
14/32
38
38/39
38/91
45
45/15
631/208/199
631/337/2019
631/337/572
Activator protein 1
Antidiabetics
Cell culture
Cell death
Cell proliferation
Cells, Cultured
Chromatin
Chromosomes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Dietary restrictions
Fibroblasts
Fibroblasts - metabolism
Forkhead protein
FOXO3 protein
Gene expression
Genomes
Humanities and Social Sciences
Humans
Hypoglycemic Agents - pharmacology
Immunoprecipitation
Life span
Metformin
Metformin - pharmacology
multidisciplinary
Rapamycin
Ribonucleic acid
RNA
Science
Science (multidisciplinary)
Serum response factor
Skin
Skin - cytology
Skin - metabolism
Transcription Factor AP-1 - metabolism
Transcription factors
title Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts
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