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

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

  • Cell. 2024 May 9;187(10):2465-2484.e22. doi: 10.1016/j.cell.2024.04.005.
Xuezhao Liu 1,  Dazhuan Eric Xin 1,  Xiaowen Zhong 2,  Chuntao Zhao 1,  Zhidan Li 3,  Liguo Zhang 1,  Adam J Dourson 4,  Lindsay Lee 5,  Shreya Mishra 5,  Arman E Bayat 1,  Eva Nicholson 1,  William L Seibel 1,  Bingfang Yan 6,  Joel Mason 7,  Bradley J Turner 7,  David G Gonsalvez 8,  William Ong 9,  Sing Yian Chew 10,  Balaram Ghosh 11,  Sung Ok Yoon 12,  Mei Xin 1,  Zhigang He 13,  Jason Tchieu 14,  Michael Wegner 15,  Klaus-Armin Nave 16,  Robin J M Franklin 17,  Ranjan Dutta 18,  Bruce D Trapp 18,  Ming Hu 5,  Matthew A Smith 19,  Michael P Jankowski 20,  Samantha K Barton 7,  Xuelian He 21,  Q Richard Lu 22
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 2 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.
  • 3 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.
  • 4 Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 5 Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 6 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45229, USA.
  • 7 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne 3052, Australia.
  • 8 Department of Anatomy and Developmental Biology, Monash University, Melbourne 3168, Australia.
  • 9 School of Chemistry, Chemical Engineering, and Biotechnology Nanyang Technological University, Singapore 637459, Singapore.
  • 10 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.
  • 11 Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, India, 500078.
  • 12 Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio.
  • 13 F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology and Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • 14 Department of Pediatrics, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 15 Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 16 Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
  • 17 Altos Labs, Cambridge Institute of Science, Granta Park, Cambridge CB21 6GP, UK.
  • 18 Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Case Western Reserve University School of Medicine, Cleveland, OH 44195, USA.
  • 19 Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA; Rebecca D. Considine Research Institute, Akron Children's Hospital, Akron, OH, USA.
  • 20 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.
  • 21 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.
  • 22 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.
PMID: 38701782 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.

Keywords

Epigenetic silencing; HDAC3 Inhibition; SREBP condensation; aging; chromatin remodeling; lipid/cholesterol biosynthesis; multiple sclerosis; myelin regeneration; oligodendrocyte; small molecule.

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