Journal Article

Smurf2‐mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke

Wu, Chen‐Shiou, Chiang, Shu‐Ya, Yu, Yung‐Luen, Shyu, Woei‐Cherng, Lin, Yu‐Hsuan, Chang, Wei‐Jung, Chou, Ruey‐Hwang, Hung, Mien‐Chie, Yeh, Su‐Peng, Hsu, Jennifer L., Hsieh, Shu‐Ching, Hung, Shih‐Chieh, Chen, Jia‐Ni, Tseng, Yen‐Ju, Yang, Cheng‐Chieh, Lee, Wei

2013

Overview

EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. Previously, we showed that EZH2 downregulation enhances neuron differentiation of human mesenchymal stem cells (hMSCs); however, the underlying mechanisms of EZH2‐regulated neuron differentiation are still unclear. Here, we identify Smurf2 as the E3 ubiquitin ligase responsible for the polyubiquitination and proteasome‐mediated degradation of EZH2, which is required for neuron differentiation. A ChIP‐on‐chip screen combined with gene microarray analysis revealed that PPARγ was the only gene involved in neuron differentiation with significant changes in both its modification and expression status during differentiation. Moreover, knocking down PPARγ prevented cells from undergoing efficient neuron differentiation. In animal model, rats implanted with intracerebral EZH2‐knocked‐down hMSCs or hMSCs plus treatment with PPARγ agonist (rosiglitazone) showed better improvement than those without EZH2 knockdown or rosiglitazone treatment after a stroke. Together, our results support Smurf2 as a regulator of EZH2 turnover to facilitate PPARγ expression, which is specifically required for neuron differentiation, providing a molecular mechanism for clinical applications in the neurodegenerative diseases. Graphical Abstract Smurf2‐mediated degradation of EZH2 enhances neuronal differentiation of human mesenchymal stem cells (hMSCs). This enables expression of PPARgamma in hMSCs, which when implanted improve recovery in a rat model of stroke.

• Publisher: Nature Publishing Group UK,WILEY‐VCH Verlag,EMBO Press,WILEY-VCH Verlag,Springer Nature
• Subject: Animal models / Animals / Bone marrow / Brain research / Cell differentiation / DNA microarrays / Enhancer of Zeste Homolog 2 Protein / Experiments / EZH2 / Gene expression / Gene silencing / Histone methyltransferase / human mesenchymal stem cells (hMSCs) / Humans / ischaemic neuronal injury / Kinases / Male / Medical research / Mesenchymal stem cells / Mesenchyme / MicroRNAs / Nervous system / Neurodegenerative diseases / Neurogenesis / neuron differentiation / Neurons - cytology / Neurons - metabolism / Polycomb Repressive Complex 2 - genetics / Polycomb Repressive Complex 2 - metabolism / Proteasomes / Proteins / Proteolysis / Rats / Rats, Sprague-Dawley / Recovery of function / Research Article / Rosiglitazone / Smurf2 / Spinal cord / Statistical analysis / Stem cell transplantation / Stem cells / Stroke / Stroke - genetics / Stroke - metabolism / Stroke - physiopathology / Therapeutic applications / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Up-Regulation