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

Xuezhao Liu; Dazhuan Eric Xin; Xiaowen Zhong; Chuntao Zhao; Zhidan Li; Liguo Zhang; Adam J Dourson; Lindsay Lee; Shreya Mishra; Arman E Bayat; Eva Nicholson; William L Seibel; Bingfang Yan; Joel Mason; Bradley J Turner; David G Gonsalvez; William Ong; Sing Yian Chew; Balaram Ghosh; Sung Ok Yoon; Mei Xin; Zhigang He; Jason Tchieu; Michael Wegner; Klaus-Armin Nave; Robin J M Franklin; Ranjan Dutta; Bruce D Trapp; Ming Hu; Matthew A Smith; Michael P Jankowski; Samantha K Barton; Xuelian He; Q Richard Lu

doi:10.1016/j.cell.2024.04.005

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. Epub 2024 May 2.

Authors

Xuezhao Liu¹, Dazhuan Eric Xin¹, Xiaowen Zhong², Chuntao Zhao¹, Zhidan Li³, Liguo Zhang¹, Adam J Dourson⁴, Lindsay Lee⁵, Shreya Mishra⁵, Arman E Bayat¹, Eva Nicholson¹, William L Seibel¹, Bingfang Yan⁶, Joel Mason⁷, Bradley J Turner⁷, David G Gonsalvez⁸, William Ong⁹, Sing Yian Chew¹⁰, Balaram Ghosh¹¹, Sung Ok Yoon¹², Mei Xin¹, Zhigang He¹³, Jason Tchieu¹⁴, Michael Wegner¹⁵, Klaus-Armin Nave¹⁶, Robin J M Franklin¹⁷, Ranjan Dutta¹⁸, Bruce D Trapp¹⁸, Ming Hu⁵, Matthew A Smith¹⁹, Michael P Jankowski²⁰, Samantha K Barton⁷, Xuelian He²¹, Q Richard Lu²²

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Differentiation / drug effects
Central Nervous System / metabolism
Demyelinating Diseases / genetics
Demyelinating Diseases / metabolism
Epigenesis, Genetic*
Humans
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / metabolism
Male
Mice
Mice, Inbred C57BL
Multiple Sclerosis / drug therapy
Multiple Sclerosis / genetics
Multiple Sclerosis / metabolism
Multiple Sclerosis / pathology
Myelin Sheath* / metabolism
Oligodendroglia* / metabolism
Organoids / drug effects
Organoids / metabolism
Regeneration / drug effects
Rejuvenation
Remyelination* / drug effects
Small Molecule Libraries / pharmacology
Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

Sterol Regulatory Element Binding Protein 1
Small Molecule Libraries

Abstract

Publication types

MeSH terms

Substances

Grants and funding