|
| Status |
Public on May 24, 2024 |
| Title |
Small-molecule-induced epigenetic rejuvenation overcomes myelinogenic barriers and stimulates myelin repair [Cut&Run] |
| Organism |
Rattus norvegicus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Failure of oligodendrocytes to remyelinate underlies diseases such as multiple sclerosis (MS). We found that epigenetic silencing prevents oligodendrocytes from producing myelin sheaths in demyelinating MS lesions. Here, we developed a transgenic reporter system to identify a small-molecule epigenetic modulator that stimulates oligodendrocyte maturation and myelin ensheathment in vitro. This compound promoted remyelination in animal models of MS and myelination of regenerated axons and increased myelin sheath lengths in human iPSC-derived organoids. Multi-omics analyses revealed that the compound induced an enhancer/super-enhancer landscape that upregulates crucial myelinogenesis-associated pathways, including RRAS2-AKT signaling, driving actin depolymerization necessary for myelin ensheathment. Strikingly, the compound also induced phase-separated nuclear condensates of SREBP1/2, which concentrate transcriptional co-activators to drive lipid and cholesterol biosynthesis. Silencing expression of a potential target of the small molecule, HDAC3, facilitated robust myelination and remyelination. Our findings suggest that small-molecule-modulated epigenome rejuvenation relieves epigenetic silencing barriers and promotes myelin repair.
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| |
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| Overall design |
cut and run of treated rat iOLs with indicated antibody
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| |
|
| Contributor(s) |
Liu X, He X, Lu QR |
| Citation(s) |
38701782 |
| |
| Submission date |
May 19, 2023 |
| Last update date |
May 24, 2024 |
| Contact name |
XUEZHAO LIU |
| E-mail(s) |
xuezhao.liu@cchmc.org
|
| Organization name |
cincinnati children's hospital medical center
|
| Street address |
3333 Burnet Ave. MLC 7013, T6.525
|
| City |
cincinnati |
| State/province |
OH |
| ZIP/Postal code |
45229 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL25029 |
NextSeq 550 (Rattus norvegicus) |
|
| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE232956 |
Small-molecule-induced epigenetic rejuvenation overcomes myelinogenic barriers and stimulates myelin repair |
|
| Relations |
| BioProject |
PRJNA974476 |
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