4.6 Article

Methyltransferase Setdb1 Promotes Osteoblast Proliferation by Epigenetically Silencing Macrod2 with the Assistance of Atf7ip

Journal

CELLS
Volume 11, Issue 16, Pages -

Publisher

MDPI
DOI: 10.3390/cells11162580

Keywords

Setdb1; cell proliferation; mechanical unloading; bone loss

Categories

Funding

  1. National Natural Science Foundation of China [31971171, 31570939]
  2. Key Pre-research Project of Manned Spaceflight [020106]
  3. Aerospace Medical Experiment Project of China Space Station [HYZHXM01006]
  4. Innovation Capability Support Program of Shaanxi, China [2020KJXX-060]

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This study reveals for the first time the role of the Atf7ip/Setdb1/Macrod2 axis in osteoblast proliferation under mechanical unloading, providing a potential protective strategy against unloading-induced bone loss.
Bone loss caused by mechanical unloading is a threat to prolonged space flight and human health. Epigenetic modifications play a crucial role in varied biological processes, but the mechanism of histone modification on unloading-induced bone loss has rarely been studied. Here, we discovered for the first time that the methyltransferase Setdb1 was downregulated under the mechanical unloading both in vitro and in vivo so as to attenuate osteoblast proliferation. Furthermore, we found these interesting processes depended on the repression of Macrod2 expression triggered by Setdb1 catalyzing the formation of H3K9me3 in the promoter region. Mechanically, we revealed that Macrod2 was upregulated under mechanical unloading and suppressed osteoblast proliferation through the GSK-3 beta/beta-catenin signaling pathway. Moreover, Atf7ip cooperatively contributed to osteoblast proliferation by changing the localization of Setdb1 under mechanical loading. In summary, this research elucidated the role of the Atf7ip/Setdb1/Macrod2 axis in osteoblast proliferation under mechanical unloading for the first time, which can be a potential protective strategy against unloading-induced bone loss.

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