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Original Article | Open Access

CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ

Ruiqi Yu1, Hong Han1, Shuxian Chu1, Yijun Ding2, Shiqi Jin1, Yufeng Wang1, Wei Jiang1, Yuting Liu1, Yongxin Zou1, Molin Wang1, Qiao Liu1, Gongping Sun3, Baichun Jiang1 ( ), Yaoqin Gong1 ( )
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
The Key Laboratory of Liquid‒Solid Structural Evolution and Processing of Materials of Ministry of Education and Institute of Liquid Metal and Casting Technology, School of Materials Science and Engineering, Shandong University, Jinan 250012, China
The Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Abstract

Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.

References

1

Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).
Crossref Google Scholar
2

Hu, L. et al. Mesenchymal stem cells: cell fate decision to osteoblast or adipocyte and application in osteoporosis treatment. Int. J. Mol. Sci. 19, 360 (2018).
Crossref Google Scholar
3

Chen, Q. et al. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ. 23, 1128–1139 (2016).
Crossref Google Scholar
4

Valenti, M. T., Dalle Carbonare, L. & Mottes, M. Osteogenic differentiation in healthy and pathological conditions. Int. J. Mol. Sci. 18, 41 (2016).
Crossref Google Scholar
5

Justesen, J. et al. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology 2, 165–171 (2001).
Crossref Google Scholar
6

Li, C. J. et al. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J. Clin. Invest. 125, 1509–1522 (2015).
Crossref Google Scholar
7

Wu, Z., Bucher, N. L. & Farmer, S. R. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell Biol. 16, 4128–4136 (1996).
Crossref Google Scholar
8

Farmer, S. R. Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006).
Crossref Google Scholar
9

Komori, T. Regulation of osteoblast differentiation by transcription factors. J. Cell Biochem. 99, 1233–1239 (2006).
Crossref Google Scholar
10

Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002).
Crossref Google Scholar
11

Kim, J. H. et al. Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts. J. Cell Biol. 204, 1063–1074 (2014).
Crossref Google Scholar
12

Birsoy, K., Chen, Z. & Friedman, J. Transcriptional regulation of adipogenesis by KLF4. Cell Metab. 7, 339–347 (2008).
Crossref Google Scholar
13

Jackson, S. & Xiong, Y. CRL4s: the CUL4-RING E3 ubiquitin ligases. Trends Biochem. Sci. 34, 562–570 (2009).
Crossref Google Scholar
14

Tarpey, P. S. et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am. J. Hum. Genet. 80, 345–352 (2007).
Crossref Google Scholar
15

Zou, Y. et al. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am. J. Hum. Genet. 80, 561–566 (2007).
Crossref Google Scholar
16

Li, P. et al. Lack of CUL4B in adipocytes promotes PPARgamma-mediated adipose tissue expansion and insulin sensitivity. Diabetes 66, 300–313 (2017).
Crossref Google Scholar
17

Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).
Crossref Google Scholar
18

Benisch, P. et al. The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors. PLoS One 7, e45142 (2012).
Crossref Google Scholar
19

Logan, M. et al. Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33, 77–80 (2002).
Crossref Google Scholar
20

Uder, C., Bruckner, S., Winkler, S., Tautenhahn, H. M. & Christ, B. Mammalian MSC from selected species: Features and applications. Cytometry A 93, 32–49 (2018).
Crossref Google Scholar
21

Li, J. et al. TGFbeta-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis. Nat. Commun. 10, 2795 (2019).
Crossref Google Scholar
22

Hu, H. et al. CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis. Cancer Cell 22, 781–795 (2012).
Crossref Google Scholar
23

Ji, Q. et al. CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression. J. Cell Sci. 127, 4679–4691 (2014).
Crossref Google Scholar
24

Manolagas, S. C. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21, 115–137 (2000).
Crossref Google Scholar
25

Gimble, J. M., Zvonic, S., Floyd, Z. E., Kassem, M. & Nuttall, M. E. Playing with bone and fat. J. Cell Biochem. 98, 251–266 (2006).
Crossref Google Scholar
26

Kim, J. M., Lin, C., Stavre, Z., Greenblatt, M. B. & Shim, J. H. Osteoblast-osteoclast communication and bone homeostasis. Cells 9, 2073 (2020).
Crossref Google Scholar
27

Garrett-Sinha, L. A., Eberspaecher, H., Seldin, M. F. & de Crombrugghe, B. A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J. Biol. Chem. 271, 31384–31390 (1996).
Crossref Google Scholar
28

Ton-That, H., Kaestner, K. H., Shields, J. M., Mahatanankoon, C. S. & Yang, V. W. Expression of the gut-enriched Kruppel-like factor gene during development and intestinal tumorigenesis. FEBS Lett. 419, 239–243 (1997).
Crossref Google Scholar
29

Michikami, I. et al. Kruppel-like factor 4 regulates membranous and endochondral ossification. Exp. Cell Res. 318, 311–325 (2012).
Crossref Google Scholar
30

Darlington, G. J., Ross, S. E. & MacDougald, O. A. The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 273, 30057–30060 (1998).
Crossref Google Scholar
31

Cao, Z., Umek, R. M. & McKnight, S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 5, 1538–1552 (1991).
Crossref Google Scholar
32

Tanaka, T., Yoshida, N., Kishimoto, T. & Akira, S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 16, 7432–7443 (1997).
Crossref Google Scholar
33

Nakayama, N. et al. A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage. Development 131, 229–240 (2004).
Crossref Google Scholar
34

Albers, J. et al. Control of bone formation by the serpentine receptor Frizzled-9. J. Cell Biol. 192, 1057–1072 (2011).
Crossref Google Scholar
35

Zhang, H., Chen, X. & Sairam, M. R. Novel genes of visceral adiposity: identification of mouse and human mesenteric estrogen-dependent adipose (MEDA)-4 gene and its adipogenic function. Endocrinology 153, 2665–2676 (2012).
Crossref Google Scholar
36

Jung, H. et al. Involvement of PTP-RQ in differentiation during adipogenesis of human mesenchymal stem cells. Biochem. Biophys. Res. Commun. 383, 252–257 (2009).
Crossref Google Scholar
37

Mortada, I. & Mortada, R. Epigenetic changes in mesenchymal stem cells differentiation. Eur. J. Med. Genet. 61, 114–118 (2018).
Crossref Google Scholar
38

Marofi, F. et al. Epigenetic mechanisms are behind the regulation of the key genes associated with the osteoblastic differentiation of the mesenchymal stem cells: The role of zoledronic acid on tuning the epigenetic changes. J. Cell Physiol. 234, 15108–15122 (2019).
Crossref Google Scholar
39

Vincent, A. & Van Seuningen, I. Epigenetics, stem cells and epithelial cell fate. Differentiation 78, 99–107 (2009).
Crossref Google Scholar
40

Qiu, J. Epigenetics: Unfinished symphony. Nature 441, 143–145 (2006).
Crossref Google Scholar
41

Yang, Y. et al. CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene 34, 104–118 (2015).
Crossref Google Scholar
42

Cho, Y. G. et al. Genetic and epigenetic analysis of the KLF4 gene in gastric cancer. APMIS 115, 802–808 (2007).
Crossref Google Scholar
43

Nakahara, Y. et al. Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma. Neoplasia 12, 20–27 (2010).
Crossref Google Scholar
44

Jiang, B. et al. Lack of Cul4b, an E3 ubiquitin ligase component, leads to embryonic lethality and abnormal placental development. PLoS One 7, e37070 (2012).
Crossref Google Scholar
45

Jiang, B. et al. DMP1 C-terminal mutant mice recapture the human ARHR tooth phenotype. J. Bone Miner Res. 25, 2155–2164 (2010).
Crossref Google Scholar
46

Zhu, H. et al. A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nat. Protoc. 5, 550–560 (2010).
Crossref Google Scholar
Bone Research
Volume 11,
December 2023
Article number: 29
DOI: 10.1038/s41413-023-00263-y
Cite this article:
Yu R, Han H, Chu S, et al. CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ. Bone Research, 2023, 11: 29. https://doi.org/10.1038/s41413-023-00263-y

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Received: 16 October 2022
Revised: 23 March 2023
Accepted: 04 April 2023
Published: 02 June 2023
© The Author(s) 2023

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