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

Autor:	Liu X; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Xin DE; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Zhong X; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45229, USA., Zhao C; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Li Z; Center for Translational Medicine, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China., Zhang L; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Dourson AJ; Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Lee L; Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Mishra S; Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Bayat AE; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Nicholson E; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Seibel WL; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Yan B; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45229, USA., Mason J; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne 3052, Australia., Turner BJ; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne 3052, Australia., Gonsalvez DG; Department of Anatomy and Developmental Biology, Monash University, Melbourne 3168, Australia., Ong W; School of Chemistry, Chemical Engineering, and Biotechnology Nanyang Technological University, Singapore 637459, Singapore., Chew SY; School of Chemistry, Chemical Engineering, and Biotechnology Nanyang Technological University, Singapore 637459, Singapore; Lee Kong Chian School of Medicine, School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore., Ghosh B; Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, India, 500078., Yoon SO; Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio., Xin M; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., He Z; F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology and Ophthalmology, Harvard Medical School, Boston, MA, USA., Tchieu J; Department of Pediatrics, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Wegner M; Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Nave KA; Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany., Franklin RJM; Altos Labs, Cambridge Institute of Science, Granta Park, Cambridge CB21 6GP, UK., Dutta R; Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Case Western Reserve University School of Medicine, Cleveland, OH 44195, USA., Trapp BD; Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Case Western Reserve University School of Medicine, Cleveland, OH 44195, USA., Hu M; Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Smith MA; Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA; Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, OH, USA., Jankowski MP; Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Pediatric Pain Research Center, Cincinnati Children's Hospital, Cincinnati, OH, USA., Barton SK; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne 3052, Australia., He X; Center for Translational Medicine, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China. Electronic address: Xuelian_he2021@scu.edu.cn., Lu QR; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: Richard.lu@cchmc.org.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 May 09; Vol. 187 (10), pp. 2465-2484.e22. Date of Electronic Publication: 2024 May 02.
DOI:	10.1016/j.cell.2024.04.005
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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