Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and 
overcomes barriers to CNS myelin regeneration

Liu, X.; Xin, D.E.; Zhong, X.; Zhao, C.; Li, Z.; Zhang, L.; Dourson, A.J.; Lee, L.; Mishra, S.; Bayat, A.E.; Nicholson, E.; Seibel, W.L.; Yan, B.; Mason, J.; Turner, B.J.; Gonsalvez, D.G.; Ong, W.; Chew, S.Y.; Ghosh, B.; Yoon, S.O.; Xin, M.; He, Z.; Tchieu, J.; Wegner, M.; Nave, K. A.; Franklin, R.J.M.; Dutta, R.; Trapp, B.D.; Hu, M.; Smith, M.A.; Jankowski, M.P.; Barton, S.K.; He, X.; Lu, Q.R.

doi:10.1016/j.cell.2024.04.005

アイテム詳細

登録内容を編集ファイル形式で保存

一時保存へ追加

タグ情報を表示リリース履歴を表示詳細要約

公開

学術論文

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration

MPS-Authors

/persons/resource/persons182320

Nave, K. A.
Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

External Resource

There are no locators available

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

フルテキスト (公開)

公開されているフルテキストはありません

付随資料 (公開)

There is no public supplementary material available

引用

Liu, X., Xin, D., Zhong, X., Zhao, C., Li, Z., Zhang, L., Dourson, A., Lee, L., Mishra, S., Bayat, A., Nicholson, E., Seibel, W., Yan, B., Mason, J., Turner, B., Gonsalvez, D., Ong, W., Chew, S., Ghosh, B., Yoon, S., Xin, M., He, Z., Tchieu, J., Wegner, M., Nave, K. A., Franklin, R., Dutta, R., Trapp, B., Hu, M., Smith, M., Jankowski, M., Barton, S., He, X., & Lu, Q. (2024). Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration. Cell, 187(10), 2465-2484.e22. doi:10.1016/j.cell.2024.04.005.

引用: https://hdl.handle.net/21.11116/0000-000F-5357-2

要旨

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.