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The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis
Osteoclasts are absorptive cells that play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role of epigenetic regulation in osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression e...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833786/ https://www.ncbi.nlm.nih.gov/pubmed/29348610 http://dx.doi.org/10.1038/s41419-017-0040-5 |
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author | Gao, Yanpan Ge, Wei |
author_facet | Gao, Yanpan Ge, Wei |
author_sort | Gao, Yanpan |
collection | PubMed |
description | Osteoclasts are absorptive cells that play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role of epigenetic regulation in osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation (H3K79me), during osteoclast formation. Using RANKL-induced RAW264.7 macrophage cells as an osteoclast differentiation model, we found that DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. In addition, DOT1L inhibition increased osteoclast surface area and accelerated bone-mass reduction in a mouse ovariectomy (OVX) model of osteoporosis without alter osteoblast differentiation. DOT1L inhibition increase reactive oxygen species (ROS) generation and autophagy activity, and cell migration in pre-osteoclasts. Moreover, it strengthened expression of osteoclast fusion and resorption-related protein CD9 and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-regulated, H3K79me2-mediated, epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease. |
format | Online Article Text |
id | pubmed-5833786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58337862018-03-06 The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis Gao, Yanpan Ge, Wei Cell Death Dis Article Osteoclasts are absorptive cells that play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role of epigenetic regulation in osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation (H3K79me), during osteoclast formation. Using RANKL-induced RAW264.7 macrophage cells as an osteoclast differentiation model, we found that DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. In addition, DOT1L inhibition increased osteoclast surface area and accelerated bone-mass reduction in a mouse ovariectomy (OVX) model of osteoporosis without alter osteoblast differentiation. DOT1L inhibition increase reactive oxygen species (ROS) generation and autophagy activity, and cell migration in pre-osteoclasts. Moreover, it strengthened expression of osteoclast fusion and resorption-related protein CD9 and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-regulated, H3K79me2-mediated, epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease. Nature Publishing Group UK 2018-01-18 /pmc/articles/PMC5833786/ /pubmed/29348610 http://dx.doi.org/10.1038/s41419-017-0040-5 Text en © The Author(s) 2018 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 Gao, Yanpan Ge, Wei The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis |
title | The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis |
title_full | The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis |
title_fullStr | The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis |
title_full_unstemmed | The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis |
title_short | The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis |
title_sort | histone methyltransferase dot1l inhibits osteoclastogenesis and protects against osteoporosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833786/ https://www.ncbi.nlm.nih.gov/pubmed/29348610 http://dx.doi.org/10.1038/s41419-017-0040-5 |
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