Rest Stability Control By EZH2 Underlies Chromatin Remodeler Switching during Microrna-Mediated Neuronal Reprogramming of Human Adult Fibroblasts | AIChE

Rest Stability Control By EZH2 Underlies Chromatin Remodeler Switching during Microrna-Mediated Neuronal Reprogramming of Human Adult Fibroblasts

Authors 

Lee, S. W. - Presenter, WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
Yoo, A., Washington University School of Medicine
Lu, Y. L., WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
Oh, Y. M., Washington University School of Medicine
Neuronal microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), have been shown to convert human adult fibroblasts to neurons when ectopically expressed through inducing epigenetic changes1-5. Yet, the mechanism by which these miRNAs, as negative regulators of their downstream target genes, lead to the activation of the neuronal program remains to be defined. Here, we reveal that miR-9/9*-124 evoke a cascade of protein stability network orchestrating the destabilization of REST6, 7, a transcriptional repressor of neuronal genes during neuronal reprogramming of human adult fibroblasts. As such, we identified a function of EZH28, 9, a lysine-methyl-transferase that stabilized REST by methylating the lysine residue of REST in human adult fibroblasts. Interestingly, REST methylation by EZH2 occurred independently of EZH2’s canonical role as a subunit of Polycomb Repressive Complex 2 (PRC2)8, 9. During neuronal reprogramming, miR-9/9*-124 led to a concurrent repression of EZH2 and REST and an important output of the downregulation of the EZH2-REST axis was the transcriptional activation of BAF53b10-12, a neuron-specific component of BAF chromatin remodeling complex essential for proper neuronal differentiation and function. Consistent with this finding, extending the expression of EZH2 during neuronal differentiation of human neural stem cells or in the developing mouse brain resulted in the failure to activate BAF53b. These results demonstrate how miRNAs trigger a cascade of protein stability controls to promote the neuronal program and the assembly of neuron-specific BAF complex during neuronal reprograming of human fibroblasts.

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