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

被引：5

作者：

Liu, Xuezhao ^{[1
]}

Xin, Dazhuan Eric ^{[1
]}

Zhong, Xiaowen ^{[1
,3
]}

Zhao, Chuntao ^{[1
]}

Li, Zhidan ^{[2
]}

Zhang, Liguo ^{[1
]}

Dourson, Adam J. ^{[4
]}

Lee, Lindsay ^{[5
]}

Mishra, Shreya ^{[5
]}

Bayat, Arman E. ^{[1
]}

Nicholson, Eva ^{[1
]}

Seibel, William L. ^{[1
]}

Yan, Bingfang ^{[3
]}

Mason, Joel ^{[6
]}

Turner, Bradley J. ^{[6
]}

Gonsalvez, David G. ^{[7
]}

Ong, William ^{[8
]}

Chew, Sing Yian ^{[8
,9
]}

Ghosh, Balaram ^{[10
]}

Yoon, Sung Ok ^{[11
]}

Xin, Mei ^{[1
]}

He, Zhigang ^{[12
,13
]}

Tchieu, Jason ^{[14
]}

Wegner, Michael ^{[15
]}

Nave, Klaus -Armin ^{[16
]}

Franklin, Robin J. M. ^{[17
]}

Dutta, Ranjan ^{[18
]}

Trapp, Bruce D. ^{[18
]}

Hu, Ming ^{[5
]}

Smith, Matthew A. ^{[19
,20
]}

Jankowski, Michael P. ^{[4
,21
]}

Barton, Samantha K. ^{[6
]}

He, Xuelian ^{[2
]}

Lu, Q. Richard ^{[1
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[2] Sichuan Univ, West China Second Univ Hosp, Ctr Translat Med,State Key Lab Biotherapy, Key Lab Birth Defects & Related Dis Women & Childr, Chengdu, Sichuan, Peoples R China

[3] Univ Cincinnati, James L Winkle Coll Pharm, Div Pharmaceut Sci, Cincinnati, OH 45229 USA

[4] Cincinnati Childrens Hosp Med Ctr, Dept Anesthesia, Div Pain Management, Cincinnati, OH USA

[5] Case Western Reserve Univ, Cleveland Clin Fdn, Lerner Res Inst, Dept Quantitat Hlth Sci,Sch Med, Cleveland, OH USA

[6] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne 3052, Australia

[7] Monash Univ, Dept Anat & Dev Biol, Melbourne 3168, Australia

[8] Nanyang Technol Univ, Sch Chem Chem Engn & Biotechnol, Singapore City 637459, Singapore

[9] Nanyang Technol Univ, Lee Kong Chian Sch Med, Sch Mat Sci & Engn, Singapore City 639798, Singapore

[10] Birla Inst Technol & Sci, Dept Pharm, Epigenet Res Lab, Pilani Hyderabad Campus, Hyderabad 500078, India

[11] Ohio State Univ, Dept Biol Chem & Pharmacol, Columbus, OH USA

[12] Harvard Med Sch, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA USA

[13] Harvard Med Sch, Dept Neurol & Ophthalmol, Boston, MA USA

[14] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Dev Biol, Cincinnati, OH USA

[15] Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Erlangen, Germany

[16] Max Planck Inst Multidisciplinary Sci, Dept Neurogenet, Gottingen, Germany

[17] Cambridge Inst Sci, Altos Labs, Granta Pk, Cambridge CB21 6GP, England

[18] Case Western Reserve Univ, Lerner Res Inst, Dept Neurosci, Cleveland Clin,Sch Med, Cleveland, OH 44195 USA

[19] Northeast Ohio Med Univ, Dept Pharmaceut Sci, Rootstown, OH USA

[20] Akron Childrens Hosp, Rebecca D Considine Res Inst, Akron, OH USA

[21] Cincinnati Childrens Hosp, Pediat Pain Res Ctr, Cincinnati, OH USA

来源：

CELL | 2024年 / 187卷 / 10期

基金：

国家重点研发计划; 美国国家卫生研究院;

关键词：

MULTIPLE-SCLEROSIS; PHASE-SEPARATION; OLIGODENDROCYTE; REMYELINATION; CHOLESTEROL; DIFFERENTIATION; SYSTEM; METABOLISM; MODULATION; MECHANISMS;

D O I：

10.1016/j.cell.2024.04.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2465 / 2484.e22

页数：43

共 3 条

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