Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells.

// Xin-Xing Zhu 1, * , Ya-Wei Yan 1, * , Demeng Chen 2 , Chun-Zhi Ai 1 , Xifeng Lu 3 , Shan-Shan Xu 1 , Shan Jiang 1 , Gen-Shen Zhong 4 , Dong-Bao Chen 5 , Yi-Zhou Jiang 1 1 Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China 2 School of Dentistry, University of California, Los Angeles, CA, USA 3 Department of Physiology, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, Guangdong, China 4 Henan Key Laboratory of Neural Regeneration and Repairment, The First affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China 5 Department of Obstetrics and Gynecology, University of California, Irvine, CA, USA * These authors contributed equally to this work Correspondence to: Yi-Zhou Jiang, email: jiangyz@szu.edu.cn Keywords: mesenchymal stem cells, HoxA-AS3, lineage specification, enhancer of zeste homolog 2, long non-coding RNA Received: June 16, 2016      Accepted: August 15, 2016      Published: August 23, 2016 ABSTRACT Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are involving in diverse cellular processes. However, their roles in reprogramming of gene expression profiles during lineage commitment and maturation of mesenchymal stem cells (MSCs) remain poorly understood. In the current study, we characterize the expression of a lncRNA, HoxA-AS3, during the differentiation of MSCs. We showed that HoxA-AS3 is increased upon adipogenic induction of MSCs, while HoxA-AS3 remains unaltered during osteogenic induction. Silencing of HoxA-AS3 in MSCs resulted in decreased adipogenesis and expression of adipogenic markers, PPARG, CEBPA, FABP4 and ADIPOQ. Conversely, knockdown of HoxA-AS3 expression in MSCs exhibited an enhanced osteogenesis and osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP1. Mechanistically, HoxA-AS3 interacts with Enhancer Of Zeste 2 (EZH2) and is required for H3 lysine-27 trimethylation (H3K27me3) of key osteogenic transcription factor Runx2. Our data reveal that HoxA-AS3 acts as an epigenetic switch that determines the lineage specification of MSC.