Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts.
Identifieur interne : 000312 ( Main/Corpus ); précédent : 000311; suivant : 000313Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts.
Auteurs : Zoe E. Gillespie ; Chenxuan Wang ; Flaviu Vadan ; Topaza Y. Yu ; Juan Ausi ; Anthony Kusalik ; Christopher H. EskiwSource :
- Scientific reports [ 2045-2322 ] ; 2019.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Transcription Factor AP-1.
- chemical , pharmacology : Hypoglycemic Agents, Metformin.
- cytology : Skin.
- metabolism : Fibroblasts, Skin.
- Cells, Cultured, Humans.
Abstract
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.
DOI: 10.1038/s41598-019-41839-1
PubMed: 30926854
PubMed Central: PMC6441003
Links to Exploration step
pubmed:30926854Le document en format XML
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<affiliation><nlm:affiliation>Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.</nlm:affiliation>
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<author><name sortKey="Wang, Chenxuan" sort="Wang, Chenxuan" uniqKey="Wang C" first="Chenxuan" last="Wang">Chenxuan Wang</name>
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<author><name sortKey="Vadan, Flaviu" sort="Vadan, Flaviu" uniqKey="Vadan F" first="Flaviu" last="Vadan">Flaviu Vadan</name>
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<author><name sortKey="Ausi, Juan" sort="Ausi, Juan" uniqKey="Ausi J" first="Juan" last="Ausi">Juan Ausi</name>
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<author><name sortKey="Kusalik, Anthony" sort="Kusalik, Anthony" uniqKey="Kusalik A" first="Anthony" last="Kusalik">Anthony Kusalik</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Metformin induces the AP-1 transcription factor network in normal dermal fibroblasts.</title>
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<author><name sortKey="Wang, Chenxuan" sort="Wang, Chenxuan" uniqKey="Wang C" first="Chenxuan" last="Wang">Chenxuan Wang</name>
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<author><name sortKey="Yu, Topaza Y" sort="Yu, Topaza Y" uniqKey="Yu T" first="Topaza Y" last="Yu">Topaza Y. Yu</name>
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<author><name sortKey="Ausi, Juan" sort="Ausi, Juan" uniqKey="Ausi J" first="Juan" last="Ausi">Juan Ausi</name>
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<series><title level="j">Scientific reports</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cells, Cultured (MeSH)</term>
<term>Fibroblasts (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Hypoglycemic Agents (pharmacology)</term>
<term>Metformin (pharmacology)</term>
<term>Skin (cytology)</term>
<term>Skin (metabolism)</term>
<term>Transcription Factor AP-1 (metabolism)</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Transcription Factor AP-1</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Hypoglycemic Agents</term>
<term>Metformin</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Skin</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Fibroblasts</term>
<term>Skin</term>
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<keywords scheme="MESH" xml:lang="en"><term>Cells, Cultured</term>
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<front><div type="abstract" xml:lang="en">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.</div>
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<Abstract><AbstractText>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.</AbstractText>
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<AffiliationInfo><Affiliation>Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.</Affiliation>
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