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

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 YoonMei 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2465-2484.e22
Journal	Cell
Volume	187
Issue number	10
DOIs	https://doi.org/10.1016/j.cell.2024.04.005
Publication status	Published - May 9 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Inc.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2024.04.005

Cite this

Liu, X., Xin, D. E., Zhong, X., Zhao, C., Li, Z., Zhang, L., Dourson, A. J., Lee, L., Mishra, S., Bayat, A. E., Nicholson, E., Seibel, W. L., Yan, B., Mason, J., Turner, B. J., Gonsalvez, D. G., Ong, W., Chew, S. Y., Ghosh, B., ... 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

@article{96c6fbd7cd9e408a994229040f91009d,

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 = "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",

}

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, RJM, Dutta, R, Trapp, BD, Hu, M, Smith, MA, Jankowski, MP, Barton, SK, He, X & Lu, QR 2024, 'Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration', Cell, vol. 187, no. 10, pp. 2465-2484.e22. https://doi.org/10.1016/j.cell.2024.04.005

TY - JOUR

T1 - Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration

AU - Liu, Xuezhao

AU - Xin, Dazhuan Eric

AU - Zhong, Xiaowen

AU - Zhao, Chuntao

AU - Li, Zhidan

AU - Zhang, Liguo

AU - Dourson, Adam J.

AU - Lee, Lindsay

AU - Mishra, Shreya

AU - Bayat, Arman E.

AU - Nicholson, Eva

AU - Seibel, William L.

AU - Yan, Bingfang

AU - Mason, Joel

AU - Turner, Bradley J.

AU - Gonsalvez, David G.

AU - Ong, William

AU - Chew, Sing Yian

AU - Ghosh, Balaram

AU - Yoon, Sung Ok

AU - Xin, Mei

AU - He, Zhigang

AU - Tchieu, Jason

AU - Wegner, Michael

AU - Nave, Klaus Armin

AU - Franklin, Robin J.M.

AU - Dutta, Ranjan

AU - Trapp, Bruce D.

AU - Hu, Ming

AU - Smith, Matthew A.

AU - Jankowski, Michael P.

AU - Barton, Samantha K.

AU - He, Xuelian

AU - Lu, Q. Richard

PY - 2024/5/9

Y1 - 2024/5/9

N2 - 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.

AB - 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.

KW - aging

KW - chromatin remodeling

KW - Epigenetic silencing

KW - HDAC3 Inhibition

KW - lipid/cholesterol biosynthesis

KW - multiple sclerosis

KW - myelin regeneration

KW - oligodendrocyte

KW - small molecule

KW - SREBP condensation

UR - http://www.scopus.com/inward/record.url?scp=85192215882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85192215882&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2024.04.005

DO - 10.1016/j.cell.2024.04.005

M3 - Article

C2 - 38701782

AN - SCOPUS:85192215882

SN - 0092-8674

VL - 187

SP - 2465-2484.e22

JO - Cell

JF - Cell

IS - 10

ER -

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

UN SDGs

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