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A novel long noncoding RNA PGC1β-OT1 regulates adipocyte and osteoblast differentiation through antagonizing miR-148a-3p

Cell Death & Differentiation (2019) | Download Citation


Long noncoding RNAs (LncRNAs) have been implicated in the regulation of adipocyte and osteoblast differentiation. However, the functional contributions of LncRNAs to adipocyte or osteoblast differentiation remain largely unexplored. In the current study we have identified a novel LncRNA named peroxisome proliferator-activated receptor γ coactivator-1β-OT1 (PGC1β-OT1). The expression levels of PGC1β-OT1 were altered during adipogenic and osteogenic differentiation from progenitor cells. 5′- and 3′-rapid amplification of cDNA ends (RACE) revealed that PGC1β-OT1 is 1759 nt in full length. Overexpression of PGC1β-OT1 in progenitor cells inhibited adipogenic differentiation, whereas silencing of endogenous PGC1β-OT1 induced adipogenic differentiation. By contrast, overexpression of PGC1β-OT1 in progenitor cells stimulated, whereas silencing of PGC1β-OT1 inhibited osteogenic differentiation. In vivo experiment showed that silencing of endogenous PGC1β-OT1 in marrow stimulated fat accumulation and decreased osteoblast differentiation in mice. Mechanism investigations revealed that PGC1β-OT1 contains a functional miR-148a-3p binding site. Overexpression of the mutant PGC1β-OT1 with mutation at the binding site failed to regulate either adipogenic or osteogenic differentiation. In vivo crosslinking combined with affinity purification studies demonstrated that PGC1β-OT1 physically associated with miR-148a-3p through the functional miR-148a-3p binding site. Furthermore, PGC1β-OT1 affected the expression of endogenous miR-148a-3p and its target gene lysine-specific demethylase 6b (KDM6B). Supplementation of miR-148a-3p in progenitor cells blocked the inhibitory effect of PGC1β-OT1 on adipocyte formation. Moreover, overexpression of Kdm6b restored the osteoblast differentiation which was inhibited by silencing of endogenous PGC1β-OT. Our studies provide evidences that the novel LncRNA PGC1β-OT1 reciprocally regulates adipogenic and osteogenic differentiation through antagonizing miR-148a-3p and enhancing KDM6B effect.

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  1. 1.

    Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME. Playing with bone and fat. J Cell Biochem. 2006;98:251–66.

  2. 2.

    Chen Q, Shou P, Zheng C, Jiang M, Cao G, Yang Q, et al. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ. 2016;23:1128–39.

  3. 3.

    Idris AI, Sophocleous A, Landao-Bassonga E, Canals M, Milligan G, Baker D, et al. Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab. 2009;10:139–47.

  4. 4.

    Yu B, Wang CY. Osteoporosis: the result of an ‘aged’ bone microenvironment. Trends Mol Med. 2016;22:641–4.

  5. 5.

    Kawai M, Rosen CJ. PPARgamma: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol. 2010;6:629–36.

  6. 6.

    Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, et al. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell. 1999;3:151–8.

  7. 7.

    Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8:727–38.

  8. 8.

    Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, et al. Core-binding factor beta interacts with Runx2 and is required for skeletal development. Nat Genet. 2002;32:633–8.

  9. 9.

    Artigas N, Gamez B, Cubillos-Rojas M, Sanchez-de Diego C, Valer JA, Pons G, et al. p53 inhibits SP7/Osterix activity in the transcriptional program of osteoblast differentiation. Cell Death Differ. 2017;24:2022–31.

  10. 10.

    Hojo H, Ohba S, He X, Lai LP, McMahon AP. Sp7/Osterix is restricted to bone-forming vertebrates where it acts as a Dlx co-factor in osteoblast specification. Dev Cell. 2016;37:238–53.

  11. 11.

    Rattanasopha S, Tongkobpetch S, Srichomthong C, Kitidumrongsook P, Suphapeetiporn K, Shotelersuk V. Absent expression of the osteoblast-specific maternally imprinted genes, DLX5 and DLX6, causes split hand/split foot malformation type I. J Med Genet. 2014;51:817–23.

  12. 12.

    Dinger ME, Pang KC, Mercer TR, Mattick JS. Differentiating protein-coding and noncoding RNA: challenges and ambiguities. PLoS Comput Biol. 2008;4:e1000176.

  13. 13.

    Cerase A, Pintacuda G, Tattermusch A, Avner P. Xist localization and function: new insights from multiple levels. Genome Biol. 2015;16:166–015-0733-y.

  14. 14.

    Lin C, Yang L. Long noncoding RNA in cancer: wiring signaling circuitry. Trends Cell Biol. 2018;28:287–301.

  15. 15.

    Zhu M, Liu J, Xiao J, Yang L, Cai M, Shen H, et al. Lnc-mg is a long non-coding RNA that promotes myogenesis. Nat Commun. 2017;8:14718.

  16. 16.

    Ramos AD, Andersen RE, Liu SJ, Nowakowski TJ, Hong SJ, Gertz C, et al. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell. 2015;16:439–47.

  17. 17.

    Ranzani V, Rossetti G, Panzeri I, Arrigoni A, Bonnal RJ, Curti S, et al. The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4. Nat Immunol. 2015;16:318–25.

  18. 18.

    Hu W, Alvarez-Dominguez JR, Lodish HF. Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep. 2012;13:971–83.

  19. 19.

    Liu J, Li Y, Lin B, Sheng Y, Yang L. HBL1 is a human long noncoding RNA that modulates cardiomyocyte development from pluripotent stem cells by counteracting MIR1. Dev Cell. 2017;42:333–348.e5.

  20. 20.

    Ghosal S, Das S, Chakrabarti J. Long noncoding RNAs: new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells. Stem Cells Dev. 2013;22:2240–53.

  21. 21.

    Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP, Noncoding RNA. gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 2010;3:ra8.

  22. 22.

    Ng SY, Johnson R, Stanton LW. Human long non-coding RNAs promote pluripotency and neuronal differentiation by association with chromatin modifiers and transcription factors. EMBO J. 2012;31:522–33.

  23. 23.

    Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010;39:925–38.

  24. 24.

    Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S, et al. LincRNA-p21 suppresses target mRNA translation. Mol Cell. 2012;47:648–55.

  25. 25.

    Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3’ UTRs via Alu elements. Nature. 2011;470:284–8.

  26. 26.

    Lu W, Zhang H, Niu Y, Wu Y, Sun W, Li H. et al. Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p. Mol Cancer. 2017;16:118-017-0685-9

  27. 27.

    Li Z, Wu X, Gu L, Shen Q, Luo W, Deng C, et al. Long non-coding RNA ATB promotes malignancy of esophageal squamous cell carcinoma by regulating miR-200b/Kindlin-2 axis. Cell Death Dis. 2017;8:e2888.

  28. 28.

    Paraskevopoulou MD, Vlachos IS, Karagkouni D, Georgakilas G, Kanellos I, Vergoulis T, et al. DIANA-LncBasev2: indexing microRNA targets on non-coding transcripts. Nucleic Acids Res. 2016;44(D1):D231–8.

  29. 29.

    Xiao T, Liu L, Li H, Sun Y, Luo H, Li T, et al. Long noncoding RNA ADINR regulates adipogenesis by transcriptionally activating C/EBPalpha. Stem Cell Rep. 2015;5:856–65.

  30. 30.

    Chen J, Liu Y, Lu S, Yin L, Zong C, Cui S. et al. The role and possible mechanism of lncRNA U90926 in modulating 3T3-L1 preadipocyte differentiation. Int J Obes (Lond). 2017;41:299–308.

  31. 31.

    Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52:101–12.

  32. 32.

    Tian L, Zheng F, Li Z, Wang H, Yuan H, Zhang X, et al. miR-148a-3p regulates adipocyte and osteoblast differentiation by targeting lysine-specific demethylase 6b. Gene. 2017;627:32–39.

  33. 33.

    Huang Y, Zheng Y, Jia L, Li W. Long noncoding RNA H19 promotes osteoblast differentiation via TGF-beta1/Smad3/HDAC signaling pathway by deriving miR-675. Stem Cells. 2015;33:3481–92.

  34. 34.

    Jin C, Jia L, Huang Y, Zheng Y, Du N, Liu Y, et al. Inhibition of lncRNA MIR31HG promotes osteogenic differentiation of human adipose-derived stem cells. Stem Cells. 2016;34:2707–20.

  35. 35.

    Rashid F, Shah A, Shan G. Long non-coding RNAs in the cytoplasm. Genom Proteom Bioinforma. 2016;14:73–80.

  36. 36.

    Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012;491:454–7.

  37. 37.

    Li MJ, Zhang J, Liang Q, Xuan C, Wu J, Jiang P, et al. Exploring genetic associations with ceRNA regulation in the human genome. Nucleic Acids Res. 2017;45:5653–65.

  38. 38.

    Bosson AD, Zamudio JR, Sharp PA. Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. Mol Cell. 2014;56:347–59.

  39. 39.

    Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.

  40. 40.

    Ye L, Fan Z, Yu B, Chang J, Al Hezaimi K, Zhou X, et al. Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell. 2012;11:50–61.

  41. 41.

    Ishida M, Shimabukuro M, Yagi S, Nishimoto S, Kozuka C, Fukuda D, et al. MicroRNA-378 regulates adiponectin expression in adipose tissue: a new plausible mechanism. PLoS ONE. 2014;9:e111537.

  42. 42.

    Park DH, Hong SJ, Salinas RD, Liu SJ, Sun SW, Sgualdino J, et al. Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis. Cell Rep. 2014;8:1290–9.

  43. 43.

    Li Q, Wang HY, Chepelev I, Zhu Q, Wei G, Zhao K, et al. Stage-dependent and locus-specific role of histone demethylase Jumonji D3 (JMJD3) in the embryonic stages of lung development. PLoS Genet. 2014;10:e1004524.

  44. 44.

    Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11:936–44.

  45. 45.

    Zhou J, Guo F, Wang G, Wang J, Zheng F, Guan X, et al. miR-20a regulates adipocyte differentiation by targeting lysine-specific demethylase 6b and transforming growth factor-beta signaling. Int J Obes (Lond). 2015;39:1282–91.

  46. 46.

    Li CJ, Cheng P, Liang MK, Chen YS, Lu Q, Wang JY, et al. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J Clin Invest. 2015;125:1509–22.

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The work was supported by grants nos. 81601864, 81501846, 81672116, and 81472040 from National Natural Science Foundation of China. The work was also partially supported by grant no. 2015KYZM09 from the Scientific Foundation of Tianjin Medical University and by grant no. 2015RC02 from Key Lab of Hormones and Development (Ministry of Health).

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  1. NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Metabolic Diseases Hospital & Institute of Endocrinology, Tianjin Medical University, 300070, Tianjin, China

    • Hairui Yuan
    • , Xiaowei Xu
    • , Xue Feng
    • , Endong Zhu
    • , Jie Zhou
    • , Guannan Wang
    • , Lijie Tian
    •  & Baoli Wang


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Correspondence to Baoli Wang.

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