PXD006448 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Inhibition of DOT1L increases osteoclast fusion and resorption and aggravates bone loss |
Description | Osteoclasts are absorptive cells and play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic regulation of osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation during osteoclast formation. 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. DOT1L inhibition also increased osteoclast area and accelerated bone mass reduction in a mouse ovariectomy (OVX) model of osteoporosis. DOT1L inhibitors did not alter osteoblast differentiation in vitro and in vivo. Proteomics data, together with bioinformatics analysis, revealed that DOT1L inhibition altered reactive oxygen species (ROS) generation, autophagy activation, and cell fusion-related protein expression. ROS generation increased, and autophagy activation and cell migration ability enhancement were verified subsequently by flow cytometry and transwell migration assays. DOT1L inhibition increased NFATc1 nuclear translocation and NF-κB activation and strengthend osteoclast fusion and expression of resorption-related protein CD9, and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-mediated H3K79me2 epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease. |
HostingRepository | PRIDE |
AnnounceDate | 2018-01-24 |
AnnouncementXML | Submission_2018-01-24_07:38:00.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Wei Ge |
SpeciesList | scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2017-05-04 02:28:08 | ID requested | |
⏵ 1 | 2018-01-24 07:38:01 | announced | |
Publication List
Gao Y, Ge W, The histone methyltransferase DOT1L inhibits osteoclastogenesis and protects against osteoporosis. Cell Death Dis, 9(2):33(2018) [pubmed] |
Keyword List
curator keyword: Biomedical |
submitter keyword: DOT1L, osteoclast, osteoporosis, proteomics |
Contact List
wei.ge |
contact affiliation | National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China |
contact email | wei.ge@chem.ox.ac.uk |
lab head | |
Wei Ge |
contact affiliation | National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences |
contact email | wei.ge@chem.ox.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD006448
- Label: PRIDE project
- Name: Inhibition of DOT1L increases osteoclast fusion and resorption and aggravates bone loss