Nac1 promotes self-renewal of embryonic stem cells through direct transcriptional regulation of c-Myc

// Yan Ruan 1, 2, * , Jianrong He 1, 3, * , Wei Wu 4, * , Ping He 4, * , Yanping Tian 1 , Lan Xiao 1 , Gaoke Liu 1 , Jiali Wang 1 , Yuda Cheng 1 , Shuo Zhang 1 , Yi Yang 5 , Jiaxiang Xiong 5 , Ke Zhao 6 , Ying Wan 2 , He Huang 3 , Junlei Zhang 1 and Rui Jian 1 1 Laboratory of Stem Cell and Developmental Biology, Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China 2 Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China 3 Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China 4 Department of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China 5 Experimental Center of Basic Medicine, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China 6 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China * These authors contributed equally to this work Correspondence to: Ying Wan, email: wanying516@foxmail.com He Huang, email: 13708385559@163.com Junlei Zhang, email: zhangjunlei@aliyun.com Keywords: embryonic stem cells, Nac1, c-Myc, transcriptional regulation, self-renewal Received: March 10, 2017      Accepted: April 27, 2017      Published: May 10, 2017 ABSTRACT The pluripotency transcriptional network in embryonic stem cells (ESCs) is composed of distinct functional units including the core and Myc units. It is hoped that dissection of the cellular functions and interconnections of network factors will aid our understanding of ESC and cancer biology. Proteomic and genomic approaches have identified Nac1 as a member of the core pluripotency network. However, previous studies have predominantly focused on the role of Nac1 in psychomotor stimulant response and cancer pathogenesis. In this study, we report that Nac1 is a self-renewal promoting factor, but is not required for maintaining pluripotency of ESCs. Loss of function of Nac1 in ESCs results in a reduced proliferation rate and an enhanced differentiation propensity. Nac1 overexpression promotes ESC proliferation and delays ESC differentiation in the absence of leukemia inhibitory factor (LIF). Furthermore, we demonstrated that Nac1 directly binds to the c-Myc promoter and regulates c-Myc transcription. The study also revealed that the function of Nac1 in promoting ESC self-renewal appears to be partially mediated by c-Myc. These findings establish a functional link between the core and c-Myc-centered networks and provide new insights into mechanisms of stemness regulation in ESCs and cancer.