@article{2de1b69684ac404ab073573206683ba1,
title = "Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration",
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 = "aging, chromatin remodeling, Epigenetic silencing, HDAC3 Inhibition, lipid/cholesterol biosynthesis, multiple sclerosis, myelin regeneration, oligodendrocyte, small molecule, SREBP condensation",
author = "Xuezhao Liu and Xin, {Dazhuan Eric} and Xiaowen Zhong and Chuntao Zhao and Zhidan Li and Liguo Zhang and Dourson, {Adam J.} and Lindsay Lee and Shreya Mishra and Bayat, {Arman E.} and Eva Nicholson and Seibel, {William L.} and Bingfang Yan and Joel Mason and Turner, {Bradley J.} and Gonsalvez, {David G.} and William Ong and Chew, {Sing Yian} and Balaram Ghosh and Yoon, {Sung Ok} and Mei Xin and Zhigang He and Jason Tchieu and Michael Wegner and Nave, {Klaus Armin} and Franklin, {Robin J.M.} and Ranjan Dutta and Trapp, {Bruce D.} and Ming Hu and Smith, {Matthew A.} and Jankowski, {Michael P.} and Barton, {Samantha K.} and Xuelian He and Lu, {Q. Richard}",
note = "Funding Information: We thank Drs. Charles Stiles, Michael Brown, Douglas Fields, and Ed Hurlock for comments and suggestions; Dr. Eric Olson for Hdac3 floxed mice; and Drs. Peng Jiang and Chengbin Xue for technical support. We are grateful to Dr. Takayoshi Suzuki for compound inhibitors. This study was funded in part by grants from the National Multiple Sclerosis Society ( NMSS-RG2110 ) to Q.R.L. and the US National Institutes of Health R01NS113965 and R01NS105715 to M.P.J., R01 AA030486 and R01 AI172959 to B.Y., and R35NS097303 to B.D.T. BioRender was used to create schematic illustrations. Funding Information: We thank Drs. Charles Stiles, Michael Brown, Douglas Fields, and Ed Hurlock for comments and suggestions; Dr. Eric Olson for Hdac3 floxed mice; and Drs. Peng Jiang and Chengbin Xue for technical support. We are grateful to Dr. Takayoshi Suzuki for compound inhibitors. Q.R.L. is supported by the National Multiple Sclerosis Society (NMSS-RG2110), X.H. is supported by the National Key R&D Program of China (2022YFA1105500), M.P.J. is supported by the US National Institutes of Health (NIH) R01NS113965 and R01NS105715, B.Y. is supported by NIH R01 AA030486 and R01 AI172959, and B.D.T. is supported by NIH R35NS097303. BioRender was used to create schematic illustrations. X.L. X.H. and Q.R.L. designed the experiments, analyzed the data, and wrote the manuscript with input from all authors. X.L. X.H. D.E.X. X.Z. and C.Z. carried out the majority of experiments. Z.L. L.Z. A.E.B. and E.N. assisted in gene-profiling analyses and animal breeding. A.J.D. and M.P.J. performed spinal cord recording. M.A.S. performed VEP recording. J.M. B.J.T. D.G.G. and S.K.B. carried out myelin organoid study. L.L. S.M. and M.H. assisted with HiChIP analysis. W.L.S. B.Y. W.O. S.Y.C. B.G. S.O.Y. M.X. Z.H. J.T. M.W. K.N. R.J.M.F. R.D. and B.D.T. provided resources and inputs and edited the manuscript. Q.R.L. supervised the overall study and revised the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",
year = "2024",
month = may,
day = "9",
doi = "10.1016/j.cell.2024.04.005",
language = "English",
volume = "187",
pages = "2465--2484.e22",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "10",
}
