Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration
Liu X, Xin DE, Zhong X, Zhao C, Li Z, Zhang L, Dourson AJ, Lee L, Mishra S, Bayat AE, Nicholson E, Seibel WL, Yan B, Mason J, Turner BJ, Gonsalvez DG, Ong W, Chew SY, Ghosh B, Yoon SO, Xin M, He Z, Tchieu J, Wegner M, Nave KA, Franklin RJ, Dutta R, Trapp BD, Hu M, Smith MA, Jankowski MP, Barton SK, He X, Lu QR (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 187
Pages Range: 2465-2484.e22
Journal Issue: 10
DOI: 10.1016/j.cell.2024.04.005
Abstract
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.
Authors with CRIS profile
Involved external institutions
Case Western Reserve University
United States (USA) (US)
Northeast Ohio Medical University (NEOMED)
United States (USA) (US)
Cincinnati Children's Hospital Medical Center
United States (USA) (US)
Birla Institute of Technology and Science (BITS)
India (IN)
Ohio State University
United States (USA) (US)
Veterans Affairs Healthcare System Boston and Harvard Medical School
United States (USA) (US)
University of Cincinnati
United States (USA) (US)
The University of Melbourne
Australia (AU)
West China Second University Hospital of Sichuan University (WCSUH-SCU)
China (CN)
Monash University
Australia (AU)
Max-Planck-Institut für Multidisziplinäre Naturwissenschaften / Max Planck Institute for Multidisciplinary Sciences
Germany (DE)
United States (USA) (US)
Northeast Ohio Medical University (NEOMED)
United States (USA) (US)
Cincinnati Children's Hospital Medical Center
United States (USA) (US)
Birla Institute of Technology and Science (BITS)
India (IN)
Ohio State University
United States (USA) (US)
Veterans Affairs Healthcare System Boston and Harvard Medical School
United States (USA) (US)
University of Cincinnati
United States (USA) (US)
The University of Melbourne
Australia (AU)
West China Second University Hospital of Sichuan University (WCSUH-SCU)
China (CN)
Monash University
Australia (AU)
Max-Planck-Institut für Multidisziplinäre Naturwissenschaften / Max Planck Institute for Multidisciplinary Sciences
Germany (DE)
How to cite
APA:
Liu, X., Xin, D.E., Zhong, X., Zhao, C., Li, Z., Zhang, L.,... Lu, Q.R. (2024). Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration. Cell, 187(10), 2465-2484.e22. https://doi.org/10.1016/j.cell.2024.04.005
MLA:
Liu, Xuezhao, et al. "Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration." Cell 187.10 (2024): 2465-2484.e22.
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