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miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1

Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly...

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Autores principales: Xie, Hong-fu, Liu, Ying-zi, Du, Rui, Wang, Ben, Chen, Meng-ting, Zhang, Yi-ya, Deng, Zhi-li, Li, Ji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386568/
https://www.ncbi.nlm.nih.gov/pubmed/28277545
http://dx.doi.org/10.1038/cddis.2017.75
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author Xie, Hong-fu
Liu, Ying-zi
Du, Rui
Wang, Ben
Chen, Meng-ting
Zhang, Yi-ya
Deng, Zhi-li
Li, Ji
author_facet Xie, Hong-fu
Liu, Ying-zi
Du, Rui
Wang, Ben
Chen, Meng-ting
Zhang, Yi-ya
Deng, Zhi-li
Li, Ji
author_sort Xie, Hong-fu
collection PubMed
description Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that DNMT1 expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and DNMT1 knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate DNMT1 with miRNA databases and found miR-377 had high homology with a sequence in the 3′-UTR of human DNMT1 mRNA. We confirmed that miR-377 was a potential regulator of DNMT1 by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting DNMT1. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes' promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and UTF1 in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of DNMT1 in HSFs. Similarly, there was a negative correlation between miR-377 and DNMT1 expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-DNMT1-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention.
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spelling pubmed-53865682017-04-27 miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1 Xie, Hong-fu Liu, Ying-zi Du, Rui Wang, Ben Chen, Meng-ting Zhang, Yi-ya Deng, Zhi-li Li, Ji Cell Death Dis Original Article Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that DNMT1 expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and DNMT1 knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate DNMT1 with miRNA databases and found miR-377 had high homology with a sequence in the 3′-UTR of human DNMT1 mRNA. We confirmed that miR-377 was a potential regulator of DNMT1 by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting DNMT1. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes' promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and UTF1 in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of DNMT1 in HSFs. Similarly, there was a negative correlation between miR-377 and DNMT1 expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-DNMT1-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention. Nature Publishing Group 2017-03 2017-03-09 /pmc/articles/PMC5386568/ /pubmed/28277545 http://dx.doi.org/10.1038/cddis.2017.75 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Xie, Hong-fu
Liu, Ying-zi
Du, Rui
Wang, Ben
Chen, Meng-ting
Zhang, Yi-ya
Deng, Zhi-li
Li, Ji
miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1
title miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1
title_full miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1
title_fullStr miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1
title_full_unstemmed miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1
title_short miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1
title_sort mir-377 induces senescence in human skin fibroblasts by targeting dna methyltransferase 1
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386568/
https://www.ncbi.nlm.nih.gov/pubmed/28277545
http://dx.doi.org/10.1038/cddis.2017.75
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