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Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling

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Abstract

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.

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Abbreviations

ALP:

Alkaline phosphatase

FABP4:

Fatty acid binding protein 4

C/EBP:

CCAAT/enhancer-binding protein

DLX:

Distal-less homeobox

DNMT3B:

DNA methyltransferase 3

HOX:

Homeobox

HP1:

Heterochromatin protein 1 (HP1)

KDM4A:

Lysine demethylase 4A

Lrp6:

Low-density lipoprotein receptor-related protein 6

MSC:

Mesenchymal stem cell

Osx:

Osterix

PPARγ:

Peroxisome proliferator-activated receptor γ

Runx2:

Runt-related transcription factor 2

SFRP4:

Secreted frizzled-related protein 4

TCF7L2:

Transcription factor 7 like 2

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Acknowledgements

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).

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  1. Qi Qi and Yi Wang contributed equally to the work.

Authors and Affiliations

  1. NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Box 126, Tianjin, 300070, China

    Qi Qi, Yi Wang, Xiaochen Wang, Yan Xie, Jie Zhou & Baoli Wang

  2. College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Junying Yang & Xiaoxia Li

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  1. Qi Qi
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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.

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Correspondence to Baoli Wang.

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Qi, Q., Wang, Y., Wang, X. et al. Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling. Cell. Mol. Life Sci. 77, 2407–2421 (2020). https://doi.org/10.1007/s00018-019-03289-w

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