Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration
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. Develo...
Gespeichert in:
| Veröffentlicht in: | Cell 2024-05, Vol.187 (10), p.2465-2484.e22 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2484.e22 |
|---|---|
| container_issue | 10 |
| container_start_page | 2465 |
| container_title | Cell |
| container_volume | 187 |
| creator | Liu, Xuezhao Xin, Dazhuan Eric Zhong, Xiaowen Zhao, Chuntao Li, Zhidan Zhang, Liguo Dourson, Adam J. Lee, Lindsay Mishra, Shreya Bayat, Arman E. Nicholson, Eva Seibel, William L. Yan, Bingfang Mason, Joel Turner, Bradley J. Gonsalvez, David G. Ong, William Chew, Sing Yian Ghosh, Balaram Yoon, Sung Ok Xin, Mei He, Zhigang Tchieu, Jason Wegner, Michael Nave, Klaus-Armin Franklin, Robin J.M. Dutta, Ranjan Trapp, Bruce D. Hu, Ming Smith, Matthew A. Jankowski, Michael P. Barton, Samantha K. He, Xuelian Lu, Q. Richard |
| description | 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.
[Display omitted]
•An epigenetic barrier impedes myelin production in multiple sclerosis lesions•Small-molecule inhibitor ESI1 promotes CNS myelin production and regeneration•ESI1 enhances (re)myelination in aged mice while reversing cognitive decline•ESI1-induced active chromatin landscape and SREBP condensation boost myelinogenesis
Oligodendrocytes in multiple sclerosis lesions exhibit epigenetic silencing that precludes myelin restoration. This study identifies a small-molecule inhibitor that counteracts epigenetic silencing, effectively enhancing myelin production and thereby promoting (re)myelination in animal models and human organoids while reversing age-related cognitive decline. |
| doi_str_mv | 10.1016/j.cell.2024.04.005 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3050939707</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0092867424004008</els_id><sourcerecordid>3050939707</sourcerecordid><originalsourceid>FETCH-LOGICAL-c356t-7db0bd2fb78365c939374339463071c274a3348a2aa46d7b0ecb78acaaddf9d73</originalsourceid><addsrcrecordid>eNp9kE1r3DAQhkVIaTZp_0AOQcdc7Iwl27Ihl2TZfEBoS7c9C1maDVpsaSvZCwv98ZWzaY-FAR3meR9GLyGXBeQFFPXNNtfY9zkDVuaQBqoTsiigFVlZCHZKFgAty5palGfkPMYtADRVVX0kZ7wRUIiGLcjv9aD6Pht8j3rqMbPOTBoNxZ19RYej1TTgdtqjU6P1ju6CH_yIka6_r-6_Ue2dQRePO-UM9XsM2g8J6FQIFkOko6fLL2s6HLC3Ltlmb3hLfCIfNqqP-Pn9vSA_H1Y_lk_Zy9fH5-XdS6Z5VY-ZMB10hm060fC60i1vuSg5b8uagyg0E6XivGwUU6qsjegAdUKVVsqYTWsEvyDXR2-6_teEcZSDjXN3yqGfouRQQbIKmFF2RHXwMQbcyF2wgwoHWYCcW5dbOSfl3LqENFCl0NW7f-oGNP8if2tOwO0RwPTLfWpFRm3RpaJtQD1K4-3__H8AuvOV5g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3050939707</pqid></control><display><type>article</type><title>Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration</title><source>ScienceDirect Journals (5 years ago - present)</source><creator>Liu, Xuezhao ; Xin, Dazhuan Eric ; Zhong, Xiaowen ; Zhao, Chuntao ; Li, Zhidan ; Zhang, Liguo ; Dourson, Adam J. ; Lee, Lindsay ; Mishra, Shreya ; Bayat, Arman E. ; Nicholson, Eva ; Seibel, William L. ; Yan, Bingfang ; Mason, Joel ; Turner, Bradley J. ; Gonsalvez, David G. ; Ong, William ; Chew, Sing Yian ; Ghosh, Balaram ; Yoon, Sung Ok ; Xin, Mei ; He, Zhigang ; Tchieu, Jason ; Wegner, Michael ; Nave, Klaus-Armin ; Franklin, Robin J.M. ; Dutta, Ranjan ; Trapp, Bruce D. ; Hu, Ming ; Smith, Matthew A. ; Jankowski, Michael P. ; Barton, Samantha K. ; He, Xuelian ; Lu, Q. Richard</creator><creatorcontrib>Liu, Xuezhao ; Xin, Dazhuan Eric ; Zhong, Xiaowen ; Zhao, Chuntao ; Li, Zhidan ; Zhang, Liguo ; Dourson, Adam J. ; Lee, Lindsay ; Mishra, Shreya ; Bayat, Arman E. ; Nicholson, Eva ; Seibel, William L. ; Yan, Bingfang ; Mason, Joel ; Turner, Bradley J. ; Gonsalvez, David G. ; Ong, William ; Chew, Sing Yian ; Ghosh, Balaram ; Yoon, Sung Ok ; Xin, Mei ; He, Zhigang ; Tchieu, Jason ; Wegner, Michael ; Nave, Klaus-Armin ; Franklin, Robin J.M. ; Dutta, Ranjan ; Trapp, Bruce D. ; Hu, Ming ; Smith, Matthew A. ; Jankowski, Michael P. ; Barton, Samantha K. ; He, Xuelian ; Lu, Q. Richard</creatorcontrib><description>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.
[Display omitted]
•An epigenetic barrier impedes myelin production in multiple sclerosis lesions•Small-molecule inhibitor ESI1 promotes CNS myelin production and regeneration•ESI1 enhances (re)myelination in aged mice while reversing cognitive decline•ESI1-induced active chromatin landscape and SREBP condensation boost myelinogenesis
Oligodendrocytes in multiple sclerosis lesions exhibit epigenetic silencing that precludes myelin restoration. This study identifies a small-molecule inhibitor that counteracts epigenetic silencing, effectively enhancing myelin production and thereby promoting (re)myelination in animal models and human organoids while reversing age-related cognitive decline.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2024.04.005</identifier><identifier>PMID: 38701782</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>aging ; chromatin remodeling ; Epigenetic silencing ; HDAC3 Inhibition ; lipid/cholesterol biosynthesis ; multiple sclerosis ; myelin regeneration ; oligodendrocyte ; small molecule ; SREBP condensation</subject><ispartof>Cell, 2024-05, Vol.187 (10), p.2465-2484.e22</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-7db0bd2fb78365c939374339463071c274a3348a2aa46d7b0ecb78acaaddf9d73</citedby><cites>FETCH-LOGICAL-c356t-7db0bd2fb78365c939374339463071c274a3348a2aa46d7b0ecb78acaaddf9d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cell.2024.04.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38701782$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Xuezhao</creatorcontrib><creatorcontrib>Xin, Dazhuan Eric</creatorcontrib><creatorcontrib>Zhong, Xiaowen</creatorcontrib><creatorcontrib>Zhao, Chuntao</creatorcontrib><creatorcontrib>Li, Zhidan</creatorcontrib><creatorcontrib>Zhang, Liguo</creatorcontrib><creatorcontrib>Dourson, Adam J.</creatorcontrib><creatorcontrib>Lee, Lindsay</creatorcontrib><creatorcontrib>Mishra, Shreya</creatorcontrib><creatorcontrib>Bayat, Arman E.</creatorcontrib><creatorcontrib>Nicholson, Eva</creatorcontrib><creatorcontrib>Seibel, William L.</creatorcontrib><creatorcontrib>Yan, Bingfang</creatorcontrib><creatorcontrib>Mason, Joel</creatorcontrib><creatorcontrib>Turner, Bradley J.</creatorcontrib><creatorcontrib>Gonsalvez, David G.</creatorcontrib><creatorcontrib>Ong, William</creatorcontrib><creatorcontrib>Chew, Sing Yian</creatorcontrib><creatorcontrib>Ghosh, Balaram</creatorcontrib><creatorcontrib>Yoon, Sung Ok</creatorcontrib><creatorcontrib>Xin, Mei</creatorcontrib><creatorcontrib>He, Zhigang</creatorcontrib><creatorcontrib>Tchieu, Jason</creatorcontrib><creatorcontrib>Wegner, Michael</creatorcontrib><creatorcontrib>Nave, Klaus-Armin</creatorcontrib><creatorcontrib>Franklin, Robin J.M.</creatorcontrib><creatorcontrib>Dutta, Ranjan</creatorcontrib><creatorcontrib>Trapp, Bruce D.</creatorcontrib><creatorcontrib>Hu, Ming</creatorcontrib><creatorcontrib>Smith, Matthew A.</creatorcontrib><creatorcontrib>Jankowski, Michael P.</creatorcontrib><creatorcontrib>Barton, Samantha K.</creatorcontrib><creatorcontrib>He, Xuelian</creatorcontrib><creatorcontrib>Lu, Q. Richard</creatorcontrib><title>Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration</title><title>Cell</title><addtitle>Cell</addtitle><description>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.
[Display omitted]
•An epigenetic barrier impedes myelin production in multiple sclerosis lesions•Small-molecule inhibitor ESI1 promotes CNS myelin production and regeneration•ESI1 enhances (re)myelination in aged mice while reversing cognitive decline•ESI1-induced active chromatin landscape and SREBP condensation boost myelinogenesis
Oligodendrocytes in multiple sclerosis lesions exhibit epigenetic silencing that precludes myelin restoration. This study identifies a small-molecule inhibitor that counteracts epigenetic silencing, effectively enhancing myelin production and thereby promoting (re)myelination in animal models and human organoids while reversing age-related cognitive decline.</description><subject>aging</subject><subject>chromatin remodeling</subject><subject>Epigenetic silencing</subject><subject>HDAC3 Inhibition</subject><subject>lipid/cholesterol biosynthesis</subject><subject>multiple sclerosis</subject><subject>myelin regeneration</subject><subject>oligodendrocyte</subject><subject>small molecule</subject><subject>SREBP condensation</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kE1r3DAQhkVIaTZp_0AOQcdc7Iwl27Ihl2TZfEBoS7c9C1maDVpsaSvZCwv98ZWzaY-FAR3meR9GLyGXBeQFFPXNNtfY9zkDVuaQBqoTsiigFVlZCHZKFgAty5palGfkPMYtADRVVX0kZ7wRUIiGLcjv9aD6Pht8j3rqMbPOTBoNxZ19RYej1TTgdtqjU6P1ju6CH_yIka6_r-6_Ue2dQRePO-UM9XsM2g8J6FQIFkOko6fLL2s6HLC3Ltlmb3hLfCIfNqqP-Pn9vSA_H1Y_lk_Zy9fH5-XdS6Z5VY-ZMB10hm060fC60i1vuSg5b8uagyg0E6XivGwUU6qsjegAdUKVVsqYTWsEvyDXR2-6_teEcZSDjXN3yqGfouRQQbIKmFF2RHXwMQbcyF2wgwoHWYCcW5dbOSfl3LqENFCl0NW7f-oGNP8if2tOwO0RwPTLfWpFRm3RpaJtQD1K4-3__H8AuvOV5g</recordid><startdate>20240509</startdate><enddate>20240509</enddate><creator>Liu, Xuezhao</creator><creator>Xin, Dazhuan Eric</creator><creator>Zhong, Xiaowen</creator><creator>Zhao, Chuntao</creator><creator>Li, Zhidan</creator><creator>Zhang, Liguo</creator><creator>Dourson, Adam J.</creator><creator>Lee, Lindsay</creator><creator>Mishra, Shreya</creator><creator>Bayat, Arman E.</creator><creator>Nicholson, Eva</creator><creator>Seibel, William L.</creator><creator>Yan, Bingfang</creator><creator>Mason, Joel</creator><creator>Turner, Bradley J.</creator><creator>Gonsalvez, David G.</creator><creator>Ong, William</creator><creator>Chew, Sing Yian</creator><creator>Ghosh, Balaram</creator><creator>Yoon, Sung Ok</creator><creator>Xin, Mei</creator><creator>He, Zhigang</creator><creator>Tchieu, Jason</creator><creator>Wegner, Michael</creator><creator>Nave, Klaus-Armin</creator><creator>Franklin, Robin J.M.</creator><creator>Dutta, Ranjan</creator><creator>Trapp, Bruce D.</creator><creator>Hu, Ming</creator><creator>Smith, Matthew A.</creator><creator>Jankowski, Michael P.</creator><creator>Barton, Samantha K.</creator><creator>He, Xuelian</creator><creator>Lu, Q. Richard</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20240509</creationdate><title>Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration</title><author>Liu, Xuezhao ; Xin, Dazhuan Eric ; Zhong, Xiaowen ; Zhao, Chuntao ; Li, Zhidan ; Zhang, Liguo ; Dourson, Adam J. ; Lee, Lindsay ; Mishra, Shreya ; Bayat, Arman E. ; Nicholson, Eva ; Seibel, William L. ; Yan, Bingfang ; Mason, Joel ; Turner, Bradley J. ; Gonsalvez, David G. ; Ong, William ; Chew, Sing Yian ; Ghosh, Balaram ; Yoon, Sung Ok ; Xin, Mei ; He, Zhigang ; Tchieu, Jason ; Wegner, Michael ; Nave, Klaus-Armin ; Franklin, Robin J.M. ; Dutta, Ranjan ; Trapp, Bruce D. ; Hu, Ming ; Smith, Matthew A. ; Jankowski, Michael P. ; Barton, Samantha K. ; He, Xuelian ; Lu, Q. Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-7db0bd2fb78365c939374339463071c274a3348a2aa46d7b0ecb78acaaddf9d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>aging</topic><topic>chromatin remodeling</topic><topic>Epigenetic silencing</topic><topic>HDAC3 Inhibition</topic><topic>lipid/cholesterol biosynthesis</topic><topic>multiple sclerosis</topic><topic>myelin regeneration</topic><topic>oligodendrocyte</topic><topic>small molecule</topic><topic>SREBP condensation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Xuezhao</creatorcontrib><creatorcontrib>Xin, Dazhuan Eric</creatorcontrib><creatorcontrib>Zhong, Xiaowen</creatorcontrib><creatorcontrib>Zhao, Chuntao</creatorcontrib><creatorcontrib>Li, Zhidan</creatorcontrib><creatorcontrib>Zhang, Liguo</creatorcontrib><creatorcontrib>Dourson, Adam J.</creatorcontrib><creatorcontrib>Lee, Lindsay</creatorcontrib><creatorcontrib>Mishra, Shreya</creatorcontrib><creatorcontrib>Bayat, Arman E.</creatorcontrib><creatorcontrib>Nicholson, Eva</creatorcontrib><creatorcontrib>Seibel, William L.</creatorcontrib><creatorcontrib>Yan, Bingfang</creatorcontrib><creatorcontrib>Mason, Joel</creatorcontrib><creatorcontrib>Turner, Bradley J.</creatorcontrib><creatorcontrib>Gonsalvez, David G.</creatorcontrib><creatorcontrib>Ong, William</creatorcontrib><creatorcontrib>Chew, Sing Yian</creatorcontrib><creatorcontrib>Ghosh, Balaram</creatorcontrib><creatorcontrib>Yoon, Sung Ok</creatorcontrib><creatorcontrib>Xin, Mei</creatorcontrib><creatorcontrib>He, Zhigang</creatorcontrib><creatorcontrib>Tchieu, Jason</creatorcontrib><creatorcontrib>Wegner, Michael</creatorcontrib><creatorcontrib>Nave, Klaus-Armin</creatorcontrib><creatorcontrib>Franklin, Robin J.M.</creatorcontrib><creatorcontrib>Dutta, Ranjan</creatorcontrib><creatorcontrib>Trapp, Bruce D.</creatorcontrib><creatorcontrib>Hu, Ming</creatorcontrib><creatorcontrib>Smith, Matthew A.</creatorcontrib><creatorcontrib>Jankowski, Michael P.</creatorcontrib><creatorcontrib>Barton, Samantha K.</creatorcontrib><creatorcontrib>He, Xuelian</creatorcontrib><creatorcontrib>Lu, Q. Richard</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Xuezhao</au><au>Xin, Dazhuan Eric</au><au>Zhong, Xiaowen</au><au>Zhao, Chuntao</au><au>Li, Zhidan</au><au>Zhang, Liguo</au><au>Dourson, Adam J.</au><au>Lee, Lindsay</au><au>Mishra, Shreya</au><au>Bayat, Arman E.</au><au>Nicholson, Eva</au><au>Seibel, William L.</au><au>Yan, Bingfang</au><au>Mason, Joel</au><au>Turner, Bradley J.</au><au>Gonsalvez, David G.</au><au>Ong, William</au><au>Chew, Sing Yian</au><au>Ghosh, Balaram</au><au>Yoon, Sung Ok</au><au>Xin, Mei</au><au>He, Zhigang</au><au>Tchieu, Jason</au><au>Wegner, Michael</au><au>Nave, Klaus-Armin</au><au>Franklin, Robin J.M.</au><au>Dutta, Ranjan</au><au>Trapp, Bruce D.</au><au>Hu, Ming</au><au>Smith, Matthew A.</au><au>Jankowski, Michael P.</au><au>Barton, Samantha K.</au><au>He, Xuelian</au><au>Lu, Q. Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2024-05-09</date><risdate>2024</risdate><volume>187</volume><issue>10</issue><spage>2465</spage><epage>2484.e22</epage><pages>2465-2484.e22</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><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.
[Display omitted]
•An epigenetic barrier impedes myelin production in multiple sclerosis lesions•Small-molecule inhibitor ESI1 promotes CNS myelin production and regeneration•ESI1 enhances (re)myelination in aged mice while reversing cognitive decline•ESI1-induced active chromatin landscape and SREBP condensation boost myelinogenesis
Oligodendrocytes in multiple sclerosis lesions exhibit epigenetic silencing that precludes myelin restoration. This study identifies a small-molecule inhibitor that counteracts epigenetic silencing, effectively enhancing myelin production and thereby promoting (re)myelination in animal models and human organoids while reversing age-related cognitive decline.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38701782</pmid><doi>10.1016/j.cell.2024.04.005</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0092-8674 |
| ispartof | Cell, 2024-05, Vol.187 (10), p.2465-2484.e22 |
| issn | 0092-8674 1097-4172 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3050939707 |
| source | ScienceDirect Journals (5 years ago - present) |
| subjects | aging chromatin remodeling Epigenetic silencing HDAC3 Inhibition lipid/cholesterol biosynthesis multiple sclerosis myelin regeneration oligodendrocyte small molecule SREBP condensation |
| title | Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-15T14%3A27%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Small-molecule-induced%20epigenetic%20rejuvenation%20promotes%20SREBP%20condensation%20and%20overcomes%20barriers%20to%20CNS%20myelin%20regeneration&rft.jtitle=Cell&rft.au=Liu,%20Xuezhao&rft.date=2024-05-09&rft.volume=187&rft.issue=10&rft.spage=2465&rft.epage=2484.e22&rft.pages=2465-2484.e22&rft.issn=0092-8674&rft.eissn=1097-4172&rft_id=info:doi/10.1016/j.cell.2024.04.005&rft_dat=%3Cproquest_cross%3E3050939707%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3050939707&rft_id=info:pmid/38701782&rft_els_id=S0092867424004008&rfr_iscdi=true |