Journal
DEVELOPMENTAL CELL
Volume 46, Issue 1, Pages 73-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2018.06.007
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Funding
- Andrew B. and Virginia C. Craig Faculty Fellowship endowment
- NIH Director's Innovator Award [DP2NS083372-01]
- Missouri Spinal Cord Injury/Disease Research Program (SCIDRP)
- Cure Alzheimer's Fund (CAF)
- Presidential Early Career Award for Scientists and Engineers (PECASE)
- NIA [RF1AG056296]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [DP2NS083372] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [RF1AG056296] Funding Source: NIH RePORTER
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The ability to convert human somatic cells efficiently to neurons facilitates the utility of patient-derived neurons for studying neurological disorders. As such, ectopic expression of neuronal microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. However, how miR-9/9*-124 break the cell fate barrier to activate the neuronal program remains to be defined. Here, we identified an anti-neurogenic function of EZH2 in fibroblasts that acts outside its role as a subunit of Polycomb Repressive Complex 2 to directly methylate and stabilize REST, a transcriptional repressor of neuronal genes. During neuronal conversion, miR-9/9*-124 induced the repression of the EZH2-REST axis by downregulating USP14, accounting for the opening of chromatin regions harboring REST binding sites. Our findings underscore the interplay between miRNAs and protein stability cascade underlying the activation of neuronal program.
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