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

  • Qi Qi
  • Yi Wang
  • Xiaochen Wang
  • Junying Yang
  • Yan Xie
  • Jie Zhou
  • Xiaoxia Li
  • Baoli WangEmail author
Original Article
  • 19 Downloads

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.

Keywords

Lysine demethylase 4A Adipocyte Osteoblast Differentiation Secreted frizzled-related protein 4 CCAAT/enhancer-binding protein α Wnt/β-catenin 

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

Notes

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).

Author contributions

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.

Supplementary material

18_2019_3289_MOESM1_ESM.doc (56 kb)
Supplementary material 1 (DOC 55 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Qi Qi
    • 1
  • Yi Wang
    • 1
  • Xiaochen Wang
    • 1
  • Junying Yang
    • 2
  • Yan Xie
    • 1
  • Jie Zhou
    • 1
  • Xiaoxia Li
    • 2
  • Baoli Wang
    • 1
    Email author
  1. 1.NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of EndocrinologyTianjin Medical UniversityTianjinChina
  2. 2.College of Basic Medical SciencesTianjin Medical UniversityTianjinChina

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