Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling
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Epigenetic modifications play a central role in cell differentiation and development. In the current study, we have recognized lysine demethylase 4A (KDM4A) as a novel epigenetic regulator of osteoblast and adipocyte differentiation. Kdm4a expression was upregulated during osteogenesis and adipogenesis of primary marrow stromal cells and established stromal ST2 line. Overexpression of wild-type Kdm4a promoted adipogenic differentiation and blocked osteogenic differentiation of the progenitor cells. This effect was largely alleviated when the catalytically dead mutation was made. Conversely, depletion or inactivation of Kdm4a in undifferentiated progenitor cells inhibited the formation of adipocytes and promoted the differentiation of osteoblasts. Mechanism explorations showed that overexpression of Kdm4a upregulated the expression of secreted frizzled-related protein 4 (Sfrp4) and CCAAT/enhancer-binding protein α (C/ebpα). Chromatin immunoprecipitation assay demonstrated that KDM4A directly bound the promoters of Sfrp4 and C/ebpα, removed the histone methylation mark H3K9me3, and reduced DNA methylation levels of CpG in promoter regions of C/ebpα and Sfrp4. Furthermore, overexpression of Kdm4a inactivated canonical Wnt signaling. Moreover, activation of canonical Wnt signaling through silencing of Sfrp4 in ST2 attenuated the inhibition of osteogenic differentiation and the enhancement of adipogenic differentiation by KDM4A. These data have identified KDM4A as a novel regulator of osteoblast and adipocyte differentiation and suggest KDM4A inhibition as a potential therapeutic target for treating metabolic disorders such as osteoporosis.
KeywordsLysine demethylase 4A Adipocyte Osteoblast Differentiation Secreted frizzled-related protein 4 CCAAT/enhancer-binding protein α Wnt/β-catenin
Fatty acid binding protein 4
DNA methyltransferase 3
Heterochromatin protein 1 (HP1)
Lysine demethylase 4A
Low-density lipoprotein receptor-related protein 6
Mesenchymal stem cell
Peroxisome proliferator-activated receptor γ
Runt-related transcription factor 2
Secreted frizzled-related protein 4
Transcription factor 7 like 2
The work was funded by National Natural Science Foundation of China (Grants nos. 81871741, 81672116 and 81772297), Natural Science Foundation of Tianjin City Municipal Science and Technology Commission (Grants nos. 18JCZDJC32200 and 18JCQNJC12900) and by Graduate student innovation fund of Tianjin Medical University (Grant no. YJSCX201803).
QQ, YW, XW, JY, YX and JZ: collection and assembly of data, data analysis and interpretation, and final approval of manuscript; XL: conception and design and final approval of manuscript; BW: conception and design, manuscript writing, and final approval of manuscript.
Compliance with ethical standards
Conflict of interest
The authors have declared no conflict of interest.
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