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A systems approach reveals that the musculoskeletal tissues development and homeostasis network
Arthritis Research & Therapy volume 14, Article number: O28 (2012)
Materials and methods
We created a whole-mount in situ hybridization database, termed EMBRYS http://embrys.jp/embrys/html/MainMenu.html, containing expression data of 1520 transcription factors and cofactors expressed in E9.5, E10.5, and E11.5 mouse embryos --a highly dynamic stage of skeletal myogenesis. This approach implicated 43 genes in regulation of embryonic myogenesis, including a transcriptional repressor, the zinc-finger protein RP58 (also known as Zfp238) .
Knockout and knockdown approaches confirmed an essential role for RP58 in skeletal myogenesis. Cell-based high-throughput transfection screening revealed that RP58 is a direct MyoD target. Microarray analysis identified two inhibitors of skeletal myogenesis, Id2 and Id3, as targets for RP58-mediated repression. Consistently, MyoD-dependent activation of the myogenic program is impaired in RP58 null fibroblasts and downregulation of Id2 and Id3 rescues MyoD's ability to promote myogenesis in these cells.
Our combined, multi-system approach reveals a MyoD-activated regulatory loop relying on RP58-mediated repression of muscle regulatory factor inhibitors. We applied our systems approaches to other locomotive tissues research including cartilage and tendon, and revealed novel molecular network regulating joint cartilage development and homeostasis via microRNA-140 [2, 3] and tendon development by Mkx .
Yokoyama S, Ito Y, Ueno-Kudoh H, Shimizu H, Uchibe K, Albini S, Mitsuoka K, Miyaki S, Kiso M, Nagai A, Hikata T, Osada T, Fukuda N, Yamashita S, Harada D, Mezzano V, Kasai M, Puri PL, Hayashizaki Y, Okado H, Hashimoto M, Asahara H: A systems approach reveals that the myogenesis genome network is regulated by the transcriptional repressor RP58. Dev Cell. 2009, 17: 836-848. 10.1016/j.devcel.2009.10.011.
Miyaki S, Sato T, Inoue A, Otsuki S, Ito Y, Yokoyama S, Kato Y, Takemoto F, Nakasa T, Yamashita S, Takada S, Lotz MK, Ueno-Kudo H, Asahara H: MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 2010, 24: 1173-1185. 10.1101/gad.1915510.
Miyaki S, Nakasa T, Otsuki S, Grogan SP, Higashiyama R, Inoue A, Kato Y, Sato T, Lotz MK, Asahara H: MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum. 2009, 60: 2723-2730. 10.1002/art.24745.
Ito Y, Toriuchi N, Yoshitaka T, Ueno-Kudoh H, Sato T, Yokoyama S, Nishida K, Akimoto T, Takahashi M, Miyaki S, Asahara H: The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci U S A. 2010, 107: 10538-10542. 10.1073/pnas.1000525107.
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Asahara, H. A systems approach reveals that the musculoskeletal tissues development and homeostasis network. Arthritis Res Ther 14 (Suppl 1), O28 (2012). https://doi.org/10.1186/ar3583
- Joint Cartilage
- Musculoskeletal Tissue
- Cartilage Development
- Tissue Research
- Dynamic Stage